Role of CD44 in activation-induced cell death: CD44-deficient mice exhibit enhanced T cell response to conventional and superantigens.
T cells upon activation are known to up-regulate CD44 expression. However, the precise function of CD44 on activated T cells is not clear. In this report, we demonstrate that signaling through CD44 plays an important role in activation-induced cell death (AICD). CD44 knockout (KO) mice had an elevated in vivo primary and in vitro secondary response to challenge with conalbumin, anti-CD3 mAb and staphylococcal enterotoxin A (SEA), which correlated with reduced AICD when compared to CD44 wild-type mice. In addition, CD44 KO mice exhibited increased delayed-type hypersensitivity response to dinitrofluorobenzene. In a model examining in vitro AICD, splenocytes from CD44 KO mice showed resistance to TCR-mediated apoptosis when compared to splenocytes from CD44 wild-type mice. In addition, signaling through CD44 led to increased apoptosis in TCR-activated but not resting T cells from CD44 wild-type mice without affecting Fas expression. Injection of SEA into mice deficient in CD44 and Fas (CD44 KO/lpr) led to an increased primary response when compared to mice that expressed CD44 but not Fas (CD44 WT/lpr), suggesting that the enhanced response to SEA was dependent on CD44 but not Fas expression. Administration of anti-CD44 mAb into CD44 wild-type mice caused a significant decrease in antigen-specific T cell response. Together, these data implicate CD44 as an important regulator of AICD in T cells. Furthermore, targeting CD44 in vivo may constitute a novel approach to induce apoptosis in activated T cells, and therefore to treat autoimmune diseases, allograft rejection and graft versus host disease.
McKallip
Robert J
RJ
Departments of Microbiology and Immunology and Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond 23298, USA.
Do
Yoon
Y
Fisher
Michael T
MT
Robertson
John L
JL
Nagarkatti
Prakash S
PS
Nagarkatti
Mitzi
M
D000818:Animals; D017209:Apoptosis / Q000276:immunology* / Q000502:physiology; D003207:Conalbumin / Q000008:administration & dosage / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D018960:Hyaluronan Receptors / Q000276:immunology* / Q000502:physiology; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology / Q000502:physiology; D018089:Superantigens / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D019014:fas Receptor / Q000096:biosynthesis
D018960:Hyaluronan Receptors; D018089:Superantigens; D019014:fas Receptor; D003207:Conalbumin