Published online before print August 28, 2007

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(Journal of Leukocyte Biology. 2007;82:1455-1465.)
© 2007 by Society for Leukocyte Biology

Modulation of CD1d-restricted NKT cell responses by CD4

Xiuxu Chen^*, Xiaohua Wang^*, Gurdyal S. Besra and Jenny E. Gumperz^*,1

^* Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; and
School of Biosciences, University of Birmingham, Birmingham, United Kingdom

¹Correspondence: Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, 1300 University Ave., Madison, WI 53705, USA. E-mail jegumperz{at}wisc.edu

CD4⁺ and CD4^– NKT cell populations have been shown to be functionally distinct, but the role of CD4 molecules in NKT cell activation is not clear. Here, we have used human CD1d-restricted NKT cell clones to investigate the contribution of CD4 to NKT cell functional responses. Coligation of CD4 with the TCR/CD3 complex resulted in enhanced cytokine secretion and increased calcium flux by CD4⁺ NKT cell clones, indicating that CD4 is functionally active in these cells. CD4 blockade specifically inhibited cytokine secretion and proliferation of CD4⁺ NKT cell clones in response to CD1d⁺ APCs but did not affect cytotoxicity, suggesting that CD4 preferentially modulates some NKT cell functional responses and not others. Anti-CD4 mAb treatment inhibited NKT cell responses to both MHC class II⁺ and MHC class II^– APCs, indicating that its effect was not due to blocking CD4 binding to MHC class II molecules on APCs. The inhibitory effect of the anti-CD4 mAb also did not require recognition of CD1d by the NKT cell, since calcium flux was reduced in response to anti-CD3 mAb stimulation. Western blot analysis revealed that anti-CD4 treatment resulted in increased phosphorylation of an inhibitory site of p56^lck (tyrosine 505). Thus, CD4 blockade interferes with the course of CD3-mediated signaling events in NKT cells. These results indicate that CD4 can contribute to NKT cell activation independently of the presence of a CD4-ligand on APCs and suggest that it preferentially modulates cytokine and proliferative responses.

Key Words: costimulation • cytotoxicity • TCR • CD3 • p56^lck • MHC class II

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