T-cell responses are initiated when a mature naive CD4 or CD8 T cell encounters an activated antigen-presenting cell displaying the appropriate peptide:MHC ligand. We will now describe the generation of effector T cells from naive T cells. The activation and differentiation of naive T cells, often called priming, is distinct from the later responses of effector T cells to antigen on their target cells, and from the responses of primed memory T cells to subsequent encounters with the same antigen. Priming of naive CD8 T cells generates cytotoxic T cells capable of directly killing pathogen-infected cells. CD4 cells develop into a diverse array of effector cell types depending on the nature of the signals they receive during priming. CD4 effector activity can also include cytotoxicity, but more frequently it involves the secretion of a set of cytokines, which direct target cells toward a more pathogen-specific response.
9-14 Cell-adhesion molecules mediate the initial interaction of naive T cells with antigen-presenting cells.
As they migrate through the cortical region of the lymph node, naive T cells bind transiently to each antigen-presenting cell that they encounter. Activated dendritic cells bind naive T cells very efficiently through interactions between LFA-1 and CD2 on the T cell and ICAM-1, ICAM-2, and CD58 on the dendritic cell (Fig. 9.20). Perhaps because of this synergy, the precise role of each adhesion molecule has been difficult to distinguish. People lacking LFA-1 can have normal T-cell responses, and this also seems to be true for genetically engineered mice lacking CD2, suggesting substantial redundancy in the function of these molecules.
The transient binding of naive T cells to antigen-presenting cells is crucial in providing time for a T cell to sample large numbers of MHC molecules for the presence of its cognate antigenic peptide. In those rare cases in which a naive T cell recognizes its peptide:MHC ligand, signaling through the T-cell receptor induces a conformational change in LFA-1 that greatly increases its affinity for ICAM-1 and ICAM-2. This conformational change is the same as that induced by signaling through CCR7 during the migration of naive T cells into a secondary lymphoid organ (see Section 9-6). The change in LFA-1 stabilizes the association between the antigen-specific T cell and the antigen-presenting cell (Fig. 9.21). The association can persist for several days, during which time the naive T cell proliferates and its progeny, which can also adhere to the antigen-presenting cell, differentiate into effector T cells.
Most encounters of T cells with antigen-presenting cells do not, however, result in the recognition of an antigen. In this case, the T cell must be able to separate efficiently from the antigen-presenting cell so that it can continue to migrate through the lymphoid tissue, eventually exiting to reenter the blood and continue circulating. Dissociation, like stable binding, may also involve signaling between the T cell and the antigen-presenting cells, but little is known of its mechanism.
Conformational change in LFA-1 increases afÿnity and prolongs cell–cell contact Subsequent binding of T-cell receptors signals LFA-1
Fig. 9.21 Transient adhesive interactions between T cells and antigen-presenting cells are stabilized by specific antigen recognition.
Fig. 9.20 Cell-surface molecules of the immunoglobulin superfamily are important in the interactions of lymphocytes with antigen-presenting cells. In the initial encounter of T cells with antigen-presenting cells, Cd2 binding to Cd58 on the antigen-presenting cell synergizes with LFa-1 binding to ICaM-1 and ICaM-2. LFa-1 is the αL:β2 integrin heterodimer Cd11a:Cd18. ICaM-1 and ICaM-2 are also known as Cd54 and Cd102, respectively.
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