The In Vivo Response of Naive CD4+ T Cells Marc K. Jenkins
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J Immunol 2014; 193:3829-3831; ; doi: 10.4049/jimmunol.1490035 http://www.jimmunol.org/content/193/8/3829
This article cites 44 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/193/8/3829.full#ref-list-1 Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscriptions Submit copyright permission requests at: http://www.aai.org/ji/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/cgi/alerts/etoc
The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 9650 Rockville Pike, Bethesda, MD 20814-3994. Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.
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The In Vivo Response of Naive CD41 T Cells Marc K. Jenkins
I
University of Minnesota, I was anxious to develop an in vivo approach for the study of peptide:MHCII-specific CD41 T cells to bolster the physiological relevance of the work. It seemed important for the approach to have the sensitivity to track the T cells in their naive state and after they became effector and memory cells during an immune response to the relevant Ag. TCR-transgenic mice had great potential in this regard because they contained an abundant supply of T cells with a known TCR specificity and could, in theory, get around the limitation that naive CD41 T cells specific for any given peptide:MHCII epitope were likely to be exceedingly rare in a normal polyclonal repertoire. Surprisingly, we found that very few of the OVA peptide:I-Ad–specific CD41 T cells in DO11.10 TCR-transgenic mice (18) showed signs of activation
Department of Microbiology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455
Abbreviations used in this article: ECDI, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; MHCII, MHC class II.
Address correspondence and reprint requests to Marc K. Jenkins, University of Minnesota, Center for Immunology, 2101 Sixth Street SE, Campus Code 2641, Minneapolis, MN 55455. E-mail address: [email protected]
Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1490035
Marc K. Jenkins
Downloaded from http://www.jimmunol.org/ at Univ of Newcstle Auchmuty Lib/Serials Sec on October 5, 2014
t is customary for the president of the American Association of Immunologists to publish a paper in the Journal of Immunology related to one’s Presidential Address at the annual meeting. One purpose of an article like this may be to give readers a sense of the scientific career path taken by an American Association of Immunologists president. So, at the risk of being presumptuous, here is my story in brief. I have spent my whole career trying to understand how CD41 T cells, the ones that use a–b TCRs to recognize peptides bound to MHC class II (MHCII) molecules (1), respond during the immune response. As a graduate student with Stephen Miller at Northwestern University, I participated in a study showing that CD41 T cells play a critical role in the delayed-type hypersensitivity reaction to protein Ags (2). During this experience, I realized that ear-swelling assays were probably only going to take us so far, so I looked for a postdoctoral position in a laboratory doing more molecular immunology. I landed a position with Ronald Schwartz in the Laboratory of Immunology at the National Institutes of Health. Ron was doing pioneering work on the fine specificity of peptide recognition by CD41 T cells using cytochrome c as a model Ag (3). It had been shown that protein Ag-pulsed splenocytes treated with the chemical 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (ECDI) induced Ag-specific immune tolerance when injected before immunization (4). My project in the Schwartz laboratory ended up focused on how ECDI inhibited the activation of pigeon cytochrome c peptide– specific Th1 clones in vitro. I found that peptide-pulsed, ECDI-treated splenocytes did not cause Th1 clones to proliferate (5). In fact, the Th1 cells became anergic, as evidenced by an inability to produce IL-2 or proliferate maximally in response to peptide Ag and viable splenocytes (5, 6). As described in Jeffrey Bluestone’s Pillars of Immunology article (7), this work, along with a similar study by Helen Quill in the Schwartz laboratory with purified peptide:MHCII complexes in planar membranes (8), provided clear experimental support for two early signal models (9, 10) positing that AgR signaling was necessary for productive lymphocyte activation but only in the context of a costimulatory signal. It may have also set the stage for later work, some from my laboratory at the University of Minnesota (11), showing that the costimulatory signal was transduced by CD28 (12–16). It is satisfying to see that CD28 blockade is now used to treat rheumatoid arthritis (17). Although my postdoctoral experience taught me the power of reductionist in vitro studies, in my own laboratory at the
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Disclosures The author has no financial conflicts of interest.
References
1. Davis, M. M., J. J. Boniface, Z. Reich, D. Lyons, J. Hampl, B. Arden, and Y. Chien. 1998. Ligand recognition by alpha beta T cell receptors. Annu. Rev. Immunol. 16: 523–544. 2. Miller, S. D., and M. K. Jenkins. 1985. In vivo effects of GK1.5 (anti-L3T4a) monoclonal antibody on induction and expression of delayed-type hypersensitivity. Cell. Immunol. 92: 414–426. 3. Schwartz, R. H. 1985. T-lymphocyte recognition of antigen in association with gene products of the major histocompatibility complex. Annu. Rev. Immunol. 3: 237–261. 4. Miller, S. D., and D. G. Hanson. 1979. Inhibition of specific immune responses by feeding protein antigens. IV. Evidence for tolerance and specific active suppression of cell-mediated immune responses to ovalbumin. J. Immunol. 123: 2344–2350. 5. Jenkins, M. K., and R. H. Schwartz. 1987. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J. Exp. Med. 165: 302–319. 6. Jenkins, M. K., D. M. Pardoll, J. Mizuguchi, T. M. Chused, and R. H. Schwartz. 1987. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc. Natl. Acad. Sci. USA 84: 5409– 5413. 7. Bour-Jordan, H., and J. A. Bluestone. 2009. How suppressor cells led to anergy, costimulation, and beyond. J. Immunol. 183: 4147–4149. 8. Quill, H., and R. H. Schwartz. 1987. Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J. Immunol. 138: 3704–3712. 9. Bretscher, P., and M. Cohn. 1970. A theory of self-nonself discrimination. Science 169: 1042–1049. 10. Lafferty, K. J., and A. J. Cunningham. 1975. A new analysis of allogeneic interactions. Aust. J. Exp. Biol. Med. Sci. 53: 27–42. 11. Jenkins, M. K., P. S. Taylor, S. D. Norton, and K. B. Urdahl. 1991. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J. Immunol. 147: 2461–2466. 12. June, C. H., J. A. Ledbetter, M. M. Gillespie, T. Lindsten, and C. B. Thompson. 1987. T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol. Cell. Biol. 7: 4472–4481. 13. Bjorndahl, J. M., S. S. Sung, J. A. Hansen, and S. M. Fu. 1989. Human T cell activation: differential response to anti-CD28 as compared to anti-CD3 monoclonal antibodies. Eur. J. Immunol. 19: 881–887. 14. Linsley, P. S., W. Brady, L. Grosmaire, A. Aruffo, N. K. Damle, and J. A. Ledbetter. 1991. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J. Exp. Med. 173: 721–730. 15. Harding, F. A., J. G. McArthur, J. A. Gross, D. H. Raulet, and J. P. Allison. 1992. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 356: 607–609. 16. Azuma, M., M. Cayabyab, D. Buck, J. H. Phillips, and L. L. Lanier. 1992. CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes. J. Exp. Med. 175: 353– 360. 17. Ruderman, E. M., and R. M. Pope. 2006. Drug Insight: abatacept for the treatment of rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 2: 654–660. 18. Murphy, K. M., A. B. Heimberger, and D. Y. Loh. 1990. Induction by antigen of intrathymic apoptosis of CD41CD81TCRlo thymocytes in vivo. Science 250: 1720–1723. 19. Kearney, E. R., K. A. Pape, D. Y. Loh, and M. K. Jenkins. 1994. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1: 327–339. 20. Marrack, P., R. Shimonkevitz, C. Hannum, K. Haskins, and J. Kappler. 1983. The major histocompatibility complex-restricted antigen receptor on T cells. IV. An antiidiotypic antibody predicts both antigen and I-specificity. J. Exp. Med. 158: 1635–1646. 21. Pape, K. A., A. Khoruts, A. Mondino, and M. K. Jenkins. 1997. Inflammatory cytokines enhance the in vivo clonal expansion and differentiation of antigen-activated CD41 T cells. J. Immunol. 159: 591–598. 22. Khoruts, A., A. Mondino, K. A. Pape, S. L. Reiner, and M. K. Jenkins. 1998. A natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism. J. Exp. Med. 187: 225–236. 23. Ingulli, E., A. Mondino, A. Khoruts, and M. K. Jenkins. 1997. In vivo detection of dendritic cell antigen presentation to CD4(1) T cells. J. Exp. Med. 185: 2133– 2141. 24. Itano, A. A., S. J. McSorley, R. L. Reinhardt, B. D. Ehst, E. Ingulli, A. Y. Rudensky, and M. K. Jenkins. 2003. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19: 47–57. 25. Garside, P., E. Ingulli, R. R. Merica, J. G. Johnson, R. J. Noelle, and M. K. Jenkins. 1998. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281: 96–99.
Downloaded from http://www.jimmunol.org/ at Univ of Newcstle Auchmuty Lib/Serials Sec on October 5, 2014
after injection of the OVA peptide (19). After scratching our heads for a long time about this odd phenomenon, we considered the idea that CD41 T cells with the identical TCR were so abundant in the intact DO11.10 mouse that they experienced inefficient activation because of competition for OVA peptide:I-Ad complexes. To test this idea, we reduced the frequency of naive DO11.10 T cells by injection into normal BALB/c mice, such that z105 of the transferred cells established residence in the secondary lymphoid organs of the recipient. The transferred T cells could easily be distinguished from the recipient’s T cells by flow cytometry using an anticlonotypic Ab specific for the DO11.10 TCR produced by Marrack, Kappler, and colleagues (20). Remarkably, injection of the OVA peptide into the adoptive recipients caused the transferred naive DO11.10 T cells to undergo a marked clonal expansion and convert to the memory cell phenotype (19). We used this simple system to publish a series of “visualization” papers documenting the effects of adjuvants on T cell activation and differentiation (19, 21, 22), early interactions between CD41 T cells and dendritic cells (23, 24), later interactions between CD41 T cells and Ag-specific B cells (19, 25), and migration of effector cells to nonlymphoid organs at the whole-body level (26). This system is still used widely today to study the in vivo T cell response, as described in Jonathan Sprent’s Pillars of Immunology article about this work (27). However, the TCR-transgenic adoptive-transfer system still suffered from the clonal competition problem, just to a lesser degree than intact TCR-transgenic mice. Lefranc¸ois’ group (28) and then my group (29) and Harty’s group (30) showed that adoptively transferred TCR-transgenic T cells differentiated inefficiently when exposed to the relevant epitope in vivo. This problem was related to the frequency of the transferred cells, because reducing it in the adoptive recipients increased the efficiency of activation. Thus, although adoptive transfer of TCR-transgenic T cells is a useful tool for the study of in vivo T cell activation, the aforementioned studies taught us that the fewest possible cells should be transferred for the best results. The issues related to the high-dose TCR-transgenic T cell adoptive-transfer system spurred us to search for a way to finally identify peptide:MHCII-specific T cells in normal polyclonal repertoires. We did so by building on the monumental discovery that peptide:MHC tetramers bind T cells with specific TCRs (31) and reports that these reagents could be used with magnetic bead–based cell techniques and flow cytometry to enrich rare specific T cells (32–38). Using peptide:MHCII tetramers in cell-enrichment mode, we detected naive peptide:MHCII-specific CD41 T cells in normal mice (39) and studied the naive to effector to memory cell transition within polyclonal repertoires (40, 41). It is gratifying to see that tetramer-based cell enrichment is now being used to study the human preimmune CD41 T cell repertoire (42, 43). In a recent chapter of this continuing story, the sensitivity of the tetramer-based cell-enrichment method brought us back to the adoptive-transfer approach to study the naive to effector cell transition but this time by transferring single naive CD41 T cells (44). I never dreamed as I was measuring swollen mouse ears and culturing T cells in 96-well plates that someday my colleagues would be tracking the fates of single epitope-specific T cells during an immune response. What a thrill.
PRESIDENT’S ADDRESS
The Journal of Immunology
36. Lucas, M., C. L. Day, J. R. Wyer, S. L. Cunliffe, A. Loughry, A. J. McMichael, and P. Klenerman. 2004. Ex vivo phenotype and frequency of influenza virus-specific CD4 memory T cells. J. Virol. 78: 7284–7287. 37. McDermott, A. B., H. M. Spiegel, J. Irsch, G. S. Ogg, and D. F. Nixon. 2001. A simple and rapid magnetic bead separation technique for the isolation of tetramer-positive virus-specific CD8 T cells. AIDS 15: 810–812. 38. Scriba, T. J., M. Purbhoo, C. L. Day, N. Robinson, S. Fidler, J. Fox, J. N. Weber, P. Klenerman, A. K. Sewell, and R. E. Phillips. 2005. Ultrasensitive detection and phenotyping of CD41 T cells with optimized HLA class II tetramer staining. J. Immunol. 175: 6334–6343. 39. Moon, J. J., H. H. Chu, M. Pepper, S. J. McSorley, S. C. Jameson, R. M. Kedl, and M. K. Jenkins. 2007. Naive CD4(1) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27: 203–213. 40. Pepper, M., J. L. Linehan, A. J. Paga´ n, T. Zell, T. Dileepan, P. P. Cleary, and M. K. Jenkins. 2010. Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat. Immunol. 11: 83–89. 41. Pepper, M., A. J. Paga´n, B. Z. Igya´rto´, J. J. Taylor, and M. K. Jenkins. 2011. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 35: 583–595. 42. Su, L. F., B. A. Kidd, A. Han, J. J. Kotzin, and M. M. Davis. 2013. Virus-specific CD4(1) memory-phenotype T cells are abundant in unexposed adults. Immunity 38: 373–383. 43. Campion, S. L., T. M. Brodie, W. Fischer, B. T. Korber, A. Rossetti, N. Goonetilleke, A. J. McMichael, and F. Sallusto. 2014. Proteome-wide analysis of HIV-specific naive and memory CD4(1) T cells in unexposed blood donors. J. Exp. Med. 211: 1273–1280. 44. Tubo, N. J., A. J. Paga´n, J. J. Taylor, R. W. Nelson, J. L. Linehan, J. M. Ertelt, E. S. Huseby, S. S. Way, and M. K. Jenkins. 2013. Single naive CD41 T cells from a diverse repertoire produce different effector cell types during infection. Cell 153: 785–796.
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26. Reinhardt, R. L., A. Khoruts, R. Merica, T. Zell, and M. K. Jenkins. 2001. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410: 101–105. 27. Sprent, J. 2013. The power of dilution: using adoptive transfer to study TCR transgenic cells. J. Immunol. 191: 5325–5326. 28. Marzo, A. L., K. D. Klonowski, A. Le Bon, P. Borrow, D. F. Tough, and L. Lefranc¸ois. 2005. Initial T cell frequency dictates memory CD81 T cell lineage commitment. Nat. Immunol. 6: 793–799. 29. Hataye, J., J. J. Moon, A. Khoruts, C. Reilly, and M. K. Jenkins. 2006. Naive and memory CD41 T cell survival controlled by clonal abundance. Science 312: 114–116. 30. Badovinac, V. P., J. S. Haring, and J. T. Harty. 2007. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8(1) T cell response to infection. Immunity 26: 827–841. 31. Altman, J. D., P. A. Moss, P. J. Goulder, D. H. Barouch, M. G. McHeyzer-Williams, J. I. Bell, A. J. McMichael, and M. M. Davis. 1996. Phenotypic analysis of antigen-specific T lymphocytes. Science 274: 94–96. 32. Day, C. L., N. P. Seth, M. Lucas, H. Appel, L. Gauthier, G. M. Lauer, G. K. Robbins, Z. M. Szczepiorkowski, D. R. Casson, R. T. Chung, et al. 2003. Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers. J. Clin. Invest. 112: 831–842. 33. Barnes, E., S. M. Ward, V. O. Kasprowicz, G. Dusheiko, P. Klenerman, and M. Lucas. 2004. Ultra-sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD81 T cells. Eur. J. Immunol. 34: 1570–1577. 34. Benlagha, K., D. G. Wei, J. Veiga, L. Teyton, and A. Bendelac. 2005. Characterization of the early stages of thymic NKT cell development. J. Exp. Med. 202: 485–492. 35. Jang, M. H., N. P. Seth, and K. W. Wucherpfennig. 2003. Ex vivo analysis of thymic CD4 T cells in nonobese diabetic mice with tetramers generated from I-A(g7)/class II-associated invariant chain peptide precursors. J. Immunol. 171: 4175–4186.
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References Subscriptions Permissions Email Alerts
J Immunol 2014; 193:3829-3831; ; doi: 10.4049/jimmunol.1490035 http://www.jimmunol.org/content/193/8/3829
This article cites 44 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/193/8/3829.full#ref-list-1 Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscriptions Submit copyright permission requests at: http://www.aai.org/ji/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/cgi/alerts/etoc
The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 9650 Rockville Pike, Bethesda, MD 20814-3994. Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.
Downloaded from http://www.jimmunol.org/ at Univ of Newcstle Auchmuty Lib/Serials Sec on October 5, 2014
This information is current as of October 5, 2014.
The In Vivo Response of Naive CD41 T Cells Marc K. Jenkins
I
University of Minnesota, I was anxious to develop an in vivo approach for the study of peptide:MHCII-specific CD41 T cells to bolster the physiological relevance of the work. It seemed important for the approach to have the sensitivity to track the T cells in their naive state and after they became effector and memory cells during an immune response to the relevant Ag. TCR-transgenic mice had great potential in this regard because they contained an abundant supply of T cells with a known TCR specificity and could, in theory, get around the limitation that naive CD41 T cells specific for any given peptide:MHCII epitope were likely to be exceedingly rare in a normal polyclonal repertoire. Surprisingly, we found that very few of the OVA peptide:I-Ad–specific CD41 T cells in DO11.10 TCR-transgenic mice (18) showed signs of activation
Department of Microbiology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455
Abbreviations used in this article: ECDI, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; MHCII, MHC class II.
Address correspondence and reprint requests to Marc K. Jenkins, University of Minnesota, Center for Immunology, 2101 Sixth Street SE, Campus Code 2641, Minneapolis, MN 55455. E-mail address: [email protected]
Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1490035
Marc K. Jenkins
Downloaded from http://www.jimmunol.org/ at Univ of Newcstle Auchmuty Lib/Serials Sec on October 5, 2014
t is customary for the president of the American Association of Immunologists to publish a paper in the Journal of Immunology related to one’s Presidential Address at the annual meeting. One purpose of an article like this may be to give readers a sense of the scientific career path taken by an American Association of Immunologists president. So, at the risk of being presumptuous, here is my story in brief. I have spent my whole career trying to understand how CD41 T cells, the ones that use a–b TCRs to recognize peptides bound to MHC class II (MHCII) molecules (1), respond during the immune response. As a graduate student with Stephen Miller at Northwestern University, I participated in a study showing that CD41 T cells play a critical role in the delayed-type hypersensitivity reaction to protein Ags (2). During this experience, I realized that ear-swelling assays were probably only going to take us so far, so I looked for a postdoctoral position in a laboratory doing more molecular immunology. I landed a position with Ronald Schwartz in the Laboratory of Immunology at the National Institutes of Health. Ron was doing pioneering work on the fine specificity of peptide recognition by CD41 T cells using cytochrome c as a model Ag (3). It had been shown that protein Ag-pulsed splenocytes treated with the chemical 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (ECDI) induced Ag-specific immune tolerance when injected before immunization (4). My project in the Schwartz laboratory ended up focused on how ECDI inhibited the activation of pigeon cytochrome c peptide– specific Th1 clones in vitro. I found that peptide-pulsed, ECDI-treated splenocytes did not cause Th1 clones to proliferate (5). In fact, the Th1 cells became anergic, as evidenced by an inability to produce IL-2 or proliferate maximally in response to peptide Ag and viable splenocytes (5, 6). As described in Jeffrey Bluestone’s Pillars of Immunology article (7), this work, along with a similar study by Helen Quill in the Schwartz laboratory with purified peptide:MHCII complexes in planar membranes (8), provided clear experimental support for two early signal models (9, 10) positing that AgR signaling was necessary for productive lymphocyte activation but only in the context of a costimulatory signal. It may have also set the stage for later work, some from my laboratory at the University of Minnesota (11), showing that the costimulatory signal was transduced by CD28 (12–16). It is satisfying to see that CD28 blockade is now used to treat rheumatoid arthritis (17). Although my postdoctoral experience taught me the power of reductionist in vitro studies, in my own laboratory at the
3830
Disclosures The author has no financial conflicts of interest.
References
1. Davis, M. M., J. J. Boniface, Z. Reich, D. Lyons, J. Hampl, B. Arden, and Y. Chien. 1998. Ligand recognition by alpha beta T cell receptors. Annu. Rev. Immunol. 16: 523–544. 2. Miller, S. D., and M. K. Jenkins. 1985. In vivo effects of GK1.5 (anti-L3T4a) monoclonal antibody on induction and expression of delayed-type hypersensitivity. Cell. Immunol. 92: 414–426. 3. Schwartz, R. H. 1985. T-lymphocyte recognition of antigen in association with gene products of the major histocompatibility complex. Annu. Rev. Immunol. 3: 237–261. 4. Miller, S. D., and D. G. Hanson. 1979. Inhibition of specific immune responses by feeding protein antigens. IV. Evidence for tolerance and specific active suppression of cell-mediated immune responses to ovalbumin. J. Immunol. 123: 2344–2350. 5. Jenkins, M. K., and R. H. Schwartz. 1987. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J. Exp. Med. 165: 302–319. 6. Jenkins, M. K., D. M. Pardoll, J. Mizuguchi, T. M. Chused, and R. H. Schwartz. 1987. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc. Natl. Acad. Sci. USA 84: 5409– 5413. 7. Bour-Jordan, H., and J. A. Bluestone. 2009. How suppressor cells led to anergy, costimulation, and beyond. J. Immunol. 183: 4147–4149. 8. Quill, H., and R. H. Schwartz. 1987. Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J. Immunol. 138: 3704–3712. 9. Bretscher, P., and M. Cohn. 1970. A theory of self-nonself discrimination. Science 169: 1042–1049. 10. Lafferty, K. J., and A. J. Cunningham. 1975. A new analysis of allogeneic interactions. Aust. J. Exp. Biol. Med. Sci. 53: 27–42. 11. Jenkins, M. K., P. S. Taylor, S. D. Norton, and K. B. Urdahl. 1991. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J. Immunol. 147: 2461–2466. 12. June, C. H., J. A. Ledbetter, M. M. Gillespie, T. Lindsten, and C. B. Thompson. 1987. T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol. Cell. Biol. 7: 4472–4481. 13. Bjorndahl, J. M., S. S. Sung, J. A. Hansen, and S. M. Fu. 1989. Human T cell activation: differential response to anti-CD28 as compared to anti-CD3 monoclonal antibodies. Eur. J. Immunol. 19: 881–887. 14. Linsley, P. S., W. Brady, L. Grosmaire, A. Aruffo, N. K. Damle, and J. A. Ledbetter. 1991. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J. Exp. Med. 173: 721–730. 15. Harding, F. A., J. G. McArthur, J. A. Gross, D. H. Raulet, and J. P. Allison. 1992. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 356: 607–609. 16. Azuma, M., M. Cayabyab, D. Buck, J. H. Phillips, and L. L. Lanier. 1992. CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes. J. Exp. Med. 175: 353– 360. 17. Ruderman, E. M., and R. M. Pope. 2006. Drug Insight: abatacept for the treatment of rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 2: 654–660. 18. Murphy, K. M., A. B. Heimberger, and D. Y. Loh. 1990. Induction by antigen of intrathymic apoptosis of CD41CD81TCRlo thymocytes in vivo. Science 250: 1720–1723. 19. Kearney, E. R., K. A. Pape, D. Y. Loh, and M. K. Jenkins. 1994. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1: 327–339. 20. Marrack, P., R. Shimonkevitz, C. Hannum, K. Haskins, and J. Kappler. 1983. The major histocompatibility complex-restricted antigen receptor on T cells. IV. An antiidiotypic antibody predicts both antigen and I-specificity. J. Exp. Med. 158: 1635–1646. 21. Pape, K. A., A. Khoruts, A. Mondino, and M. K. Jenkins. 1997. Inflammatory cytokines enhance the in vivo clonal expansion and differentiation of antigen-activated CD41 T cells. J. Immunol. 159: 591–598. 22. Khoruts, A., A. Mondino, K. A. Pape, S. L. Reiner, and M. K. Jenkins. 1998. A natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism. J. Exp. Med. 187: 225–236. 23. Ingulli, E., A. Mondino, A. Khoruts, and M. K. Jenkins. 1997. In vivo detection of dendritic cell antigen presentation to CD4(1) T cells. J. Exp. Med. 185: 2133– 2141. 24. Itano, A. A., S. J. McSorley, R. L. Reinhardt, B. D. Ehst, E. Ingulli, A. Y. Rudensky, and M. K. Jenkins. 2003. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity 19: 47–57. 25. Garside, P., E. Ingulli, R. R. Merica, J. G. Johnson, R. J. Noelle, and M. K. Jenkins. 1998. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281: 96–99.
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after injection of the OVA peptide (19). After scratching our heads for a long time about this odd phenomenon, we considered the idea that CD41 T cells with the identical TCR were so abundant in the intact DO11.10 mouse that they experienced inefficient activation because of competition for OVA peptide:I-Ad complexes. To test this idea, we reduced the frequency of naive DO11.10 T cells by injection into normal BALB/c mice, such that z105 of the transferred cells established residence in the secondary lymphoid organs of the recipient. The transferred T cells could easily be distinguished from the recipient’s T cells by flow cytometry using an anticlonotypic Ab specific for the DO11.10 TCR produced by Marrack, Kappler, and colleagues (20). Remarkably, injection of the OVA peptide into the adoptive recipients caused the transferred naive DO11.10 T cells to undergo a marked clonal expansion and convert to the memory cell phenotype (19). We used this simple system to publish a series of “visualization” papers documenting the effects of adjuvants on T cell activation and differentiation (19, 21, 22), early interactions between CD41 T cells and dendritic cells (23, 24), later interactions between CD41 T cells and Ag-specific B cells (19, 25), and migration of effector cells to nonlymphoid organs at the whole-body level (26). This system is still used widely today to study the in vivo T cell response, as described in Jonathan Sprent’s Pillars of Immunology article about this work (27). However, the TCR-transgenic adoptive-transfer system still suffered from the clonal competition problem, just to a lesser degree than intact TCR-transgenic mice. Lefranc¸ois’ group (28) and then my group (29) and Harty’s group (30) showed that adoptively transferred TCR-transgenic T cells differentiated inefficiently when exposed to the relevant epitope in vivo. This problem was related to the frequency of the transferred cells, because reducing it in the adoptive recipients increased the efficiency of activation. Thus, although adoptive transfer of TCR-transgenic T cells is a useful tool for the study of in vivo T cell activation, the aforementioned studies taught us that the fewest possible cells should be transferred for the best results. The issues related to the high-dose TCR-transgenic T cell adoptive-transfer system spurred us to search for a way to finally identify peptide:MHCII-specific T cells in normal polyclonal repertoires. We did so by building on the monumental discovery that peptide:MHC tetramers bind T cells with specific TCRs (31) and reports that these reagents could be used with magnetic bead–based cell techniques and flow cytometry to enrich rare specific T cells (32–38). Using peptide:MHCII tetramers in cell-enrichment mode, we detected naive peptide:MHCII-specific CD41 T cells in normal mice (39) and studied the naive to effector to memory cell transition within polyclonal repertoires (40, 41). It is gratifying to see that tetramer-based cell enrichment is now being used to study the human preimmune CD41 T cell repertoire (42, 43). In a recent chapter of this continuing story, the sensitivity of the tetramer-based cell-enrichment method brought us back to the adoptive-transfer approach to study the naive to effector cell transition but this time by transferring single naive CD41 T cells (44). I never dreamed as I was measuring swollen mouse ears and culturing T cells in 96-well plates that someday my colleagues would be tracking the fates of single epitope-specific T cells during an immune response. What a thrill.
PRESIDENT’S ADDRESS
The Journal of Immunology
36. Lucas, M., C. L. Day, J. R. Wyer, S. L. Cunliffe, A. Loughry, A. J. McMichael, and P. Klenerman. 2004. Ex vivo phenotype and frequency of influenza virus-specific CD4 memory T cells. J. Virol. 78: 7284–7287. 37. McDermott, A. B., H. M. Spiegel, J. Irsch, G. S. Ogg, and D. F. Nixon. 2001. A simple and rapid magnetic bead separation technique for the isolation of tetramer-positive virus-specific CD8 T cells. AIDS 15: 810–812. 38. Scriba, T. J., M. Purbhoo, C. L. Day, N. Robinson, S. Fidler, J. Fox, J. N. Weber, P. Klenerman, A. K. Sewell, and R. E. Phillips. 2005. Ultrasensitive detection and phenotyping of CD41 T cells with optimized HLA class II tetramer staining. J. Immunol. 175: 6334–6343. 39. Moon, J. J., H. H. Chu, M. Pepper, S. J. McSorley, S. C. Jameson, R. M. Kedl, and M. K. Jenkins. 2007. Naive CD4(1) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27: 203–213. 40. Pepper, M., J. L. Linehan, A. J. Paga´ n, T. Zell, T. Dileepan, P. P. Cleary, and M. K. Jenkins. 2010. Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat. Immunol. 11: 83–89. 41. Pepper, M., A. J. Paga´n, B. Z. Igya´rto´, J. J. Taylor, and M. K. Jenkins. 2011. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 35: 583–595. 42. Su, L. F., B. A. Kidd, A. Han, J. J. Kotzin, and M. M. Davis. 2013. Virus-specific CD4(1) memory-phenotype T cells are abundant in unexposed adults. Immunity 38: 373–383. 43. Campion, S. L., T. M. Brodie, W. Fischer, B. T. Korber, A. Rossetti, N. Goonetilleke, A. J. McMichael, and F. Sallusto. 2014. Proteome-wide analysis of HIV-specific naive and memory CD4(1) T cells in unexposed blood donors. J. Exp. Med. 211: 1273–1280. 44. Tubo, N. J., A. J. Paga´n, J. J. Taylor, R. W. Nelson, J. L. Linehan, J. M. Ertelt, E. S. Huseby, S. S. Way, and M. K. Jenkins. 2013. Single naive CD41 T cells from a diverse repertoire produce different effector cell types during infection. Cell 153: 785–796.
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26. Reinhardt, R. L., A. Khoruts, R. Merica, T. Zell, and M. K. Jenkins. 2001. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410: 101–105. 27. Sprent, J. 2013. The power of dilution: using adoptive transfer to study TCR transgenic cells. J. Immunol. 191: 5325–5326. 28. Marzo, A. L., K. D. Klonowski, A. Le Bon, P. Borrow, D. F. Tough, and L. Lefranc¸ois. 2005. Initial T cell frequency dictates memory CD81 T cell lineage commitment. Nat. Immunol. 6: 793–799. 29. Hataye, J., J. J. Moon, A. Khoruts, C. Reilly, and M. K. Jenkins. 2006. Naive and memory CD41 T cell survival controlled by clonal abundance. Science 312: 114–116. 30. Badovinac, V. P., J. S. Haring, and J. T. Harty. 2007. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8(1) T cell response to infection. Immunity 26: 827–841. 31. Altman, J. D., P. A. Moss, P. J. Goulder, D. H. Barouch, M. G. McHeyzer-Williams, J. I. Bell, A. J. McMichael, and M. M. Davis. 1996. Phenotypic analysis of antigen-specific T lymphocytes. Science 274: 94–96. 32. Day, C. L., N. P. Seth, M. Lucas, H. Appel, L. Gauthier, G. M. Lauer, G. K. Robbins, Z. M. Szczepiorkowski, D. R. Casson, R. T. Chung, et al. 2003. Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers. J. Clin. Invest. 112: 831–842. 33. Barnes, E., S. M. Ward, V. O. Kasprowicz, G. Dusheiko, P. Klenerman, and M. Lucas. 2004. Ultra-sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD81 T cells. Eur. J. Immunol. 34: 1570–1577. 34. Benlagha, K., D. G. Wei, J. Veiga, L. Teyton, and A. Bendelac. 2005. Characterization of the early stages of thymic NKT cell development. J. Exp. Med. 202: 485–492. 35. Jang, M. H., N. P. Seth, and K. W. Wucherpfennig. 2003. Ex vivo analysis of thymic CD4 T cells in nonobese diabetic mice with tetramers generated from I-A(g7)/class II-associated invariant chain peptide precursors. J. Immunol. 171: 4175–4186.
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