Recognition of antigens by T lymphocytes

T and B lymphocytes recognize antigens in fundamentally different ways. Both T and B lymphocytes have extensive antigen-specific receptor repertoires and can react with a very large number of different antigens, each being able to distinguish among more than 107 distinct antigenic determinants. However, entirely different genes which are located on different chromosomes are used to construct their cell surface receptors for specific antigens. Nevertheless, they use similar mechanisms to produce their antigen receptors, employing a limited number of gene segments which are combined in many different ways to construct a very large number of conformationally distinct polypeptides. The T cell receptor (TCR) for antigen consists of a heterodimeric structure, which in most T cells consists of a and 0 chains. However, a minority of peripheral T cells (approximately 5%) employ a TCR composed of structurally related but distinct y and S polypeptides. Such T cells are the dominant population in most surface epithelia in mice. There is generally allelic exclusion in the expression of genes encoding TCR peptides so that a given T lymphocyte expresses only one functional a and one (3 gene or one y and one 8 gene. The use of a and (3 or y and 8 chain polypeptides in various heterodimeric combinations contributes to the very large repertoire. Somatic mutation, which contributes to the affinity maturation of antibodies, does not appear to take place in T lymphocytes.

T lymphocytes react with antigen fragments associated with molecules of the MHC expressed by the individual in which the T lymphocytes arose. During the course of maturation in the thymus, T lymphocytes appear to be positively selected for the ability to recognize self antigens, but those T lymphocytes which react too strongly with self antigens appear to be negatively selected and deleted. The vast majority of cells which enter the thymus fail to survive these selection processes and die; probably less than 5% of thymocytes find their way to peripheral lymphoid tissues as mature T lymphocytes.

In addition to rearrangements of genes encoding the TCR and subsequent selection events, maturation of T lymphocytes in the thymus also involves sequential expression of a number of lineage-specific molecules, including CD4 and CD 8 which distinguish different T lymphocyte subsets. The most immature cells in the thymus express neither of these cell surface structures and have not rearranged their TCR genes. The TCR is expressed first in cells which express both CD4 and CD8; CD4+ and CD8+ subsets of T lymphocytes develop from this 'double-positive' population. Expression of CD4 is associated conventionally with 'helper' cell functions and CD 8 expression with cytolytic activity, but these distinctions are by no means absolute. Many CD4+ T cells have cytolytic capabilities, and at least some CD8+ T cells can carry out helper functions. The mutually exclusive expression of CD4 or CD 8 correlates better with the class of MHC antigen which serves as the restriction element for antigen recognition than it does with function: CD4+ T cells usually recognize antigenic peptides associated with class II MHC molecules, while CD8+ T cells are usually restricted to recognition of peptides associated with class I MHC molecules. Both CD4 and CD8 have 'coreceptor' function, probably by bringing the protein tyrosine kinase Ick into the TCR-antigen complex.

Full activation of CD4+ T cells requires two signals: one delivered through TCR, and a second 'costimulatory' signal which is not antigen specific. Stimulation of the TCR alone induces anergy, defined as the long-lived inability to secrete interleu-kin 2 (IL-2) and proliferate in response to antigenic stimulation. CD28 has been identified as the dominant costimulatory molecule expressed by T cells. While stimulation through CD28 alone has little effect, interaction of CD28 with B7 on antigen-presenting cells (APCs) in conjunction with TCR engagement augments significantly the secretion of multiple cytokines. A full understanding of the phenomenon of costimulation is complicated by the fact that these counterreceptor families have multiple members: CTLA-4, which is structurally similar to CD28, also binds to B7-1 and B7-2, which also are related structurally. These B7 family members arc not expressed concordantly on all ceil types, and their expression is differentially regulated. While most resting T cells express CD28, CTLA-4 is expressed only on activated T cells. An attractive model proposes that interactions between CD28 and B7-2 provide costimulation for T cell activation, while interactions between CTLA-4 and B7-1, both of which are expressed later in immune responses, terminate ongoing responses.

Several other cell surface molecules are involved in the interaction between T lymphocytes and APCs. CD2, expressed on all human thymocytes and peripheral T cells, interacts with LFA-3, a broadly distributed glycoprotein. The T lymphocyte integrin, LFA-1, interacts with ICAM-1, a heavily glycosylated and widely expressed molecule, and with ICAM-2. There are probably additional cell surface structures which are important in interactions of T lymphocytes with other cells. While these structures enhance cell-to-cell contact, many of them also appear to be involved in cell activation, either participating directly in signaling events or indirectly by modulating, either positively or negatively, signals induced through the TCR.

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