The antigen T cell receptor (TCR)-CD3 complexes present on the cell surface of CD4؉ T lymphocytes and T cell lines express CD3⑀ chain isoforms with different isoelectric points (pI), with important structural and functional consequences. The pI values of the isoforms fit the predicted pI values of CD3⑀ chains lacking one, two, and three negatively charged amino acid residues present in the N-terminal region. Different T cells have different ratios of CD3⑀ chain isoforms. At a high pI, degraded CD3⑀ isoforms can be better recognized by certain anti-CD3 monoclonal antibodies such as YCD3-1, the ability of which to bind to the TCR-CD3 complex is directly correlated with the pI of CD3⑀. The abundance of CD3⑀ isoforms can be modified by treatment of T cells with the proteinase inhibitor phenanthroline. In addition, these CD3⑀ isoforms have functional importance. This is shown, first, by the different structure of TCR-CD3 complexes in cells possessing different amounts of isoforms (as observed in surface biotinylation experiments), by their different antigen responses, and by the stronger interaction between low pI CD3⑀ isoforms and the TCR. Second, incubation of cells with phenanthroline diminished the proportion of degraded high pI CD3⑀ isoforms, but also the ability of the cells to deliver early TCR activation signals. Third, cells expressing mutant CD3⑀ chains lacking N-terminal acid residues showed facilitated recognition by antibody YCD3-1 and enhanced TCR-mediated activation. Furthermore, the binding avidity of antibody YCD3-1 was different in distinct thymus populations. These results suggest that changes in CD3⑀ N-terminal chains might help to fine-tune the response of the TCR to its ligands in distinct activation situations or in thymus selection.

The inducible co-stimulator (ICOS, CD278) is essential to the efficient development of normal and pathological immune reactions. Since ICOS-deficient mice have enhanced susceptibility to experimental allergic encephalomyelitis (EAE), we have functionally analyzed a CD4+ICOS+ population comprising 6-15% of all CD4+ T cells in secondary lymphoid organs of unmanipulated wild-type mice and checked for their ability to suppress EAE. In C57BL/6 mice, CD4+ICOS+ cells were a major source of cytokines including IFN-gamma, IL-2, IL-4, IL-10 or IL-17A. Upon activation, these cells showed preferentially enhanced production of IL-4 or IL-10 but inhibited IFN-gamma production. In contrast, CD4+ICOS- cells mainly produced IFN-gamma. Interestingly, CD4+ICOS+ cells partially suppressed the proliferation of CD4+ICOS- or CD4+CD25- lymphocytes 'in vitro' by an IL-10-dependent mechanism. Furthermore, CD4+ICOS+ activated and expanded under appropriate conditions yielded a population enriched in cells producing IL-10 and T(h)2 cytokines that also suppressed the proliferation of CD4+CD25- lymphocytes. CD4+ICOS+ cells, before or after expansion in vitro, reduced the severity of EAE when transferred to ICOS-deficient mice. In the same EAE model, lymph node cells from ICOS-deficient mice receiving ICOS+ cells showed reduced IL-17A production and enhanced IL-10 secretion upon antigen activation in vitro. Thus, naturally occurring CD4+ICOS+ cells, expanded or not in vitro, are functionally relevant cells able of protecting ICOS-deficient mice from severe EAE.

The T-cell antigen receptor complex (TCR/CD3) is a cell surface structure that defines the T lymphocyte lineage, where it fulfills two basic functions, namely antigen recognition and triggering of signals needed to mount adequate responses to foreign aggression and/or to undergo differentiation. Knowing the precise structure of the complex in terms of its components and their relative arrangement and interactions before and after antigen recognition is essential to understand how ligand binding transforms into functionally relevant T-cell responses. These include not only full responses to foreign peptide antigens by mature T-cells, but also other phenomena like modulation ofT-cell activation with altered peptide ligands, positive and negative selection ofthymocytes, alloreactivity and autoimmune reactions. A wealth of new data has accumulated in recent years on the structure of TCR/antigen complexes and CD3 polypeptides and on the stoichiometry of the TCR/CD3 complex and intersubunit interactions. In this review, we discuss how these data fit into a meaningful model of the TCR/CD3 function.

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