Inhibition of TCR-mediated shedding of L-selectin (CD62L) on human and mouse CD4+ T cells by metalloproteinase inhibition: analysis of the regulation of Th1/Th2 function.
The generation of a productive primary immune response is dependent on the ability of naïve T lymphocytes to recirculate through peripheral lymph organs to encounter specific antigen. The process of naïve CD4(+) T cell entry into lymph nodes correlates with cell surface expression of L-selectin (CD62L), which mediates early tethering and rolling events to endothelium prior to entry. Here, we demonstrate that surface expression of CD62L enhances CD4(+) T cell activation in vitro. The synthetic hydroxamate metalloproteinase inhibitor (BB-3103), specifically inhibits activation-induced shedding of CD62L from CD4(+) T cells by TCR cross-linking and lowers proliferation in part by reducing rapid tyrosine phosphorylation of zeta-associated protein 70 kDa (ZAP-70) and by increasing cytosolic free Ca(2+) concentration mobilization. BB-3103 also inhibited the proliferative response of both murine CD4(+) Th1 and Th2 subsets in vitro but the inhibitory effects were sustained only in Th2-type cells. Similarly, BB-3103 mediated prolonged inhibition of allergen-dependent peripheral T cell proliferation in atopic dermatitis patients but not in healthy controls. Analysis of CD62L expression on murine CD4(+) T cell subsets revealed that surface expression was maintained on Th1 cells but not Th2 cells. The differential effects of BB-3103 on primed effector CD4(+) T cells may provide new insights into generating therapeutic agents capable of redressing the Th2/Th1 imbalance in allergic diseases.
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D019041:L-Selectin / Q000032:analysis / Q000502:physiology*; D008213:Lymphocyte Activation; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*
C108282:BB 3103; D016207:Cytokines; D006877:Hydroxamic Acids; D011948:Receptors, Antigen, T-Cell; D019041:L-Selectin; D008666:Metalloendopeptidases; D002118:Calcium