New insights into T-cell antigen receptor structure and signal transduction Andrew Howard
C. Chan, Bryan A. Irving
Hughes Medical Institute,
Recent
University
studies have provided
the T-cell antigen
receptor
of tyrosine
Current
functioning
in immunology
of
Both
of cellular substrates.
1992, 4:24&251
that T-cell specific components other than the Ti, CD3, and 6 subunits are not required for efficient TCR assembly and expression. More importantly, addition of either CD3y or CD36 to HeIa cells expressing Ti a, f3,CD38 and 6 was sufficient for surface TCR expression [5**]. This result suggests that two distinct types of TCRs could be expressed in T cells, each composed of pairs of either s-6 or EY dimers exclusively. The Iindings of two studies, one utilizing y or 6 specific antibodies [6*], the other a y-deficient T-cell clone [7*] are consistent with this notion. Moreover, the latter study demonstrated that these y-deficient receptors were functional.
The T-cell antigen receptor (TCR) has evolved as a highly complex oligomeric receptor consisting of as many as seven distinct integral membrane proteins. The TCR must first recognize and bind its cognate ligand, then translate this binding event into intracellular signaling events that ultimately result in the appropriate cellular responses. While the two clonally variant TCR chains, Ti u and j!I, together define the antigen specificity of a given TCR, the function of the non-covalently associated invariant chains, CD3 (y, 6, E), 5, and rl has been unclear. Recent data have provided direct evidence that these chains act to couple antigen recognition to intracellular signal transduction pathways and raise questions regarding the requirement for such structural complexity within the receptor. This review will focus on the recent major advances made towards understanding how the complex structure of the TCR relates to its function in signal transduction and towards elucidating the mechanisms by which its stimulation results in cellular activation.
and stoichiometry
structure
function.
signaling modules that regulate
kinases and phosphorylation
Opinion
Weiss
San Francisco, USA
insights into how the complex
Introduction
Structure
of California,
relates to its signal transduction
the CD3 and 6 subunits contain the activation
and Arthur
Given the evidence for two E heterodimers within a receptor complex, a revised model of the TCR has emerged based on the acidic and basic amino acids present in the transmembrane domains of each of the TCR subunits (Fig. 1). These charges, three basic residues in the Ti heterodimer, and a single acidic residue in each of the CD3 chains are thought to facilitate proper receptor assembly. Thus, the receptor would include two Ti heterodimers (total positive charge of six), in association with two E heterodimers composed of either EY or ~8 and one c family dimer (total negative charge’ of six). The finding of structural heterogeneity within TCR complexes has naturally led to speculation regarding the ability of the distinct receptor types to couple differentially, in a qualitative or quantitative fashion, to signaling machinery. For instance, by altering the levels of CD3y and CD36 expressed in receptors during development, differential cellular responses to a given stimulus (i.e., antigen .combined with MHC) may occur. Alternatively, distinct ligands may exist that could bind to the immunoglobulinlike extracellular domains of EY or ~6 pairs, preferentially stimulating one or the other receptor isoform. However, although there is precedent for varying ratios of EY and ~8 within T-cell clones [6-l, there is little evidence to date supporting either a differential coupling by these receptor types or the existence of ligands for CD3. Inter-
of the TCR
The complexity of the TCR has hindered progress in determining the precise stoichiometry of its subunits. Since the discovery of CD3s dimers within a receptor complex [ 1,2], it has been presumed that the Ti subunits exist in an obligatory association with both CD3sy and CD3s6 pairs, and a dimer composed of members of the 6 family: 6, rl, or FcsRl y [3], Until recently, new insights have largely been made using somatic variants deficient in one or more receptor subunits. With the successful genetic reconstitution of the receptor on the surface of nonhematopoietic Chinese hamster ovary (CHO) [4], and HeIa cell lines [ 5-1, two groups have provided evidence
Abbreviations IL-interleukin;
IP-inositol
phospholipid;
PI-phosphatidyl
SH-src-homology;
246
@
Current
inositol; PLC-phospholipase
TCR-T-cell
Biology
receptor;
Ltd ISSN
Th-T
0952-7915
helper.
C; PTK-protein
tyrosine
kinase;
T-ceil
Ti
receptor
structure
and signal transduction
Chan,
Irving,
Weiss
Ti
Fig. l.Model
of the T-cell receptor (TCR). The stoichiometry okthe subunits i@based on an equal number of acidic and basic residues in the transmembrane domains of the component chains, The’CD36& and CD3y& subunits are spatially separated since the y and 6 chains do not interact and receptors can be expressed in th; apparent absence of either the 6 or y chains, A homodimer of the 6 subunit C
C. Chan, Bryan A. Irving
Hughes Medical Institute,
Recent
University
studies have provided
the T-cell antigen
receptor
of tyrosine
Current
functioning
in immunology
of
Both
of cellular substrates.
1992, 4:24&251
that T-cell specific components other than the Ti, CD3, and 6 subunits are not required for efficient TCR assembly and expression. More importantly, addition of either CD3y or CD36 to HeIa cells expressing Ti a, f3,CD38 and 6 was sufficient for surface TCR expression [5**]. This result suggests that two distinct types of TCRs could be expressed in T cells, each composed of pairs of either s-6 or EY dimers exclusively. The Iindings of two studies, one utilizing y or 6 specific antibodies [6*], the other a y-deficient T-cell clone [7*] are consistent with this notion. Moreover, the latter study demonstrated that these y-deficient receptors were functional.
The T-cell antigen receptor (TCR) has evolved as a highly complex oligomeric receptor consisting of as many as seven distinct integral membrane proteins. The TCR must first recognize and bind its cognate ligand, then translate this binding event into intracellular signaling events that ultimately result in the appropriate cellular responses. While the two clonally variant TCR chains, Ti u and j!I, together define the antigen specificity of a given TCR, the function of the non-covalently associated invariant chains, CD3 (y, 6, E), 5, and rl has been unclear. Recent data have provided direct evidence that these chains act to couple antigen recognition to intracellular signal transduction pathways and raise questions regarding the requirement for such structural complexity within the receptor. This review will focus on the recent major advances made towards understanding how the complex structure of the TCR relates to its function in signal transduction and towards elucidating the mechanisms by which its stimulation results in cellular activation.
and stoichiometry
structure
function.
signaling modules that regulate
kinases and phosphorylation
Opinion
Weiss
San Francisco, USA
insights into how the complex
Introduction
Structure
of California,
relates to its signal transduction
the CD3 and 6 subunits contain the activation
and Arthur
Given the evidence for two E heterodimers within a receptor complex, a revised model of the TCR has emerged based on the acidic and basic amino acids present in the transmembrane domains of each of the TCR subunits (Fig. 1). These charges, three basic residues in the Ti heterodimer, and a single acidic residue in each of the CD3 chains are thought to facilitate proper receptor assembly. Thus, the receptor would include two Ti heterodimers (total positive charge of six), in association with two E heterodimers composed of either EY or ~8 and one c family dimer (total negative charge’ of six). The finding of structural heterogeneity within TCR complexes has naturally led to speculation regarding the ability of the distinct receptor types to couple differentially, in a qualitative or quantitative fashion, to signaling machinery. For instance, by altering the levels of CD3y and CD36 expressed in receptors during development, differential cellular responses to a given stimulus (i.e., antigen .combined with MHC) may occur. Alternatively, distinct ligands may exist that could bind to the immunoglobulinlike extracellular domains of EY or ~6 pairs, preferentially stimulating one or the other receptor isoform. However, although there is precedent for varying ratios of EY and ~8 within T-cell clones [6-l, there is little evidence to date supporting either a differential coupling by these receptor types or the existence of ligands for CD3. Inter-
of the TCR
The complexity of the TCR has hindered progress in determining the precise stoichiometry of its subunits. Since the discovery of CD3s dimers within a receptor complex [ 1,2], it has been presumed that the Ti subunits exist in an obligatory association with both CD3sy and CD3s6 pairs, and a dimer composed of members of the 6 family: 6, rl, or FcsRl y [3], Until recently, new insights have largely been made using somatic variants deficient in one or more receptor subunits. With the successful genetic reconstitution of the receptor on the surface of nonhematopoietic Chinese hamster ovary (CHO) [4], and HeIa cell lines [ 5-1, two groups have provided evidence
Abbreviations IL-interleukin;
IP-inositol
phospholipid;
PI-phosphatidyl
SH-src-homology;
246
@
Current
inositol; PLC-phospholipase
TCR-T-cell
Biology
receptor;
Ltd ISSN
Th-T
0952-7915
helper.
C; PTK-protein
tyrosine
kinase;
T-ceil
Ti
receptor
structure
and signal transduction
Chan,
Irving,
Weiss
Ti
Fig. l.Model
of the T-cell receptor (TCR). The stoichiometry okthe subunits i@based on an equal number of acidic and basic residues in the transmembrane domains of the component chains, The’CD36& and CD3y& subunits are spatially separated since the y and 6 chains do not interact and receptors can be expressed in th; apparent absence of either the 6 or y chains, A homodimer of the 6 subunit C
