Cytotoxic T lymphocytes (CTL) play a crucial role in immune defense, killing virus infected or tumor cells. In addition to the TCR, accessory receptors are involved in mediating adhesion to target cells and activating functional responses through interaction with their ligands on the target. Novel methods have been developed for preparing artificial cell surface constructs where the ligand composition of the surface can be precisely controlled, allowing study of the relative contributions of the individual receptors and way they act in concert to activate T cells. Work done during the previous granting period examined TCR-dependent activation of adhesion and cosignaling by CD8 and integrins of effector CTL. The results support a model that can account at the molecular level for many of the properties of CTL killing of target cells. Using the TCR transgenic mice, studies of the regulation of these receptors on precursor CD8+ cells have begun. Preliminary results show that adhesion regulation of CD8 and the integrin receptors is complex, and varies with the differentiation state of the cell. At the simplest level, surface expression regulates receptor function. However, expressed receptors can be either (i) inactive, unable to be acutely upregulated by a TCR signal, (ii) active, acutely upregulated upon TCR engagement, or (iii) constitutively active. CD8 is inactive on naive CD8+ cells but acquires the ability to be acutely upregulated via the TCR concomitant with differentiation of the cells to lytic effectors. LFA-1, in contrast, becomes constitutively active early during differentiation. The current proposal describes plans to further characterized regulation of the adhesion receptors (CD8, LFA-1 and integrins) on CD8+ cells at all stages of differentiation from thymic precursors to memory effector cells.
Specific aims i nclude: (1) To determine the regulation of CD8- and integrin-mediated adhesion functions to naive CD8+ T cells, (2) To determine the regulation of CD8- and integrin-mediated adhesion functions for memory CD8+ cells, and primary versus secondary effector (CTL, (3) To determine the regulation of CD8- and integrin-mediated adhesion functions for CD4+CD8+ thymocytes, and (4) To determine if the CD8 beta chain is required for TCR-activated binding of CD8 to class I. The planned experiments are expected to provide significant new insights into how the activation of CD8+ T cells by class I/peptide complexes is controlled during differentiation, and provide explanations at the molecular level for several aspects of this process in both the thymus and periphery.
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