The long term objective of this proposal is to establish the physiologic importance of CD43 as a regulator of T-lymphocyte trafficking. CD43 is an integral membrane glycoprotein expressed by virtually all cells of hematopoietic origin in a differentiation- and activation-specific manner. The physiologic function of CD43 remains controversial. In vitro, CD43 negatively regulates T-lymphocyte adhesion and activation. In vivo, recent findings in our laboratory indicate that CD43 regulates T- lymphocyte homing to peripheral lymph nodes, possibly by interfering with l-selectin-mediated adhesion. These findings suggest a novel and potentially important mechanism for the control of T-lymphocyte trafficking, a process critical to maintaining the integrity of the immune system.
The specific aims of this proposal are (1) to establish the effect of CD43 on L-selectin-mediated lymphocyte adhesion to high endothelial venules in peripheral lymph nodes; (2) to determine the importance of CD43's topographical distribution for its adhesion regulatory effects, and ; (3) to determine the effect of CD43 on T- lymphocyte homing to secondary lymphoid organs. A novel model of intravital videomicroscopy that can visualize the lymph node microcirculation, and an in vitro flow chamber apparatus will be used to assess CD43's effect on L-selectin-mediated lymphocyte adhesion. CD43 chimeric mutant constructs will be used to generate cells that express CD43 in specific topographical locations in order to determine the functional importance of CD43's natural topographical distribution. The effect of CD43 on regulating T-lymphocyte homing to secondary lymphoid tissues will be determined by measuring the in vivo distribution of flourochrome-labeled T-lymphocytes derived from lymph nodes and spleen of wild-type and CD43-KO mice. These studies are important because they will establish """"""""anti-adhesion"""""""" as a legitimate and physiologically relevant function of a leukocyte surface determinant and they will provide new insights into how the complex process of lymphocyte trafficking is regulated.
| Fratazzi, C; Manjunath, N; Arbeit, R D et al. (2000) A macrophage invasion mechanism for mycobacteria implicating the extracellular domain of CD43. J Exp Med 192:183-92 |
| Carlow, D A; Ardman, B; Ziltener, H J (1999) A novel CD8 T cell-restricted CD45RB epitope shared by CD43 is differentially affected by glycosylation. J Immunol 163:1441-8 |
| Sperling, A I; Sedy, J R; Manjunath, N et al. (1998) TCR signaling induces selective exclusion of CD43 from the T cell-antigen-presenting cell contact site. J Immunol 161:6459-62 |
