CD4-unhelped CD8 + T cells are functionally defective T cells primed in the absence of CD4 + T cell help. Given the co-stimulatory role of natural-killer group 2, member D protein (NKG2D) on CD8 + T cells, we investigated its ability to rescue these immunologically impotent cells. We demonstrate that augmented co-stimulation through NKG2D during priming paradoxically rescues memory, but not effector, CD8 + T cell responses. NKG2D-mediated rescue is characterized by reversal of elevated transcription factor T-box expressed in T cells (T-bet) expression and recovery of interleukin-2 and interferon-γ production and cytolytic responses. Rescue is abrogated in CD8 + T cells lacking NKG2D. Augmented co-stimulation through NKG2D confers a high rate of survival to mice lacking CD4 + T cells in a CD4-dependent influenza model and rescues HIV-specific CD8 + T cell responses from CD4-deficient HIV-positive donors. These findings demonstrate that augmented co-stimulation through NKG2D is effective in rescuing CD4-unhelped CD8 + T cells from their pathophysiological fate and may provide therapeutic benefits.
Bibliographical noteFunding Information:
US National Cancer Institute Cancer Center Support Grant 5P30CA014599-35) for CD4 depletion antibody production. HMG2D-specific antibody was used with permission from H. Yagita (Juntendo University School of Medicine). This work was supported in part by the American Cancer Society (ACSLIB112496-RSG) to J.A.G.-P.; American Cancer Society-Illinois Division (Young Investigator Award Grant 07-20) to J.A.G.-P.; Croatian Ministry of Science, Education and Sports (062-0621261-1271), as well as the Croatian-Israeli Grant to B.P.; the US National Institutes of Health R21CA127037 and 1P01CA154778-01A1 to J.A.G.-P., PO1AI082971 to L.A.-H., K22AI077714 to P.G.T.; T32 Immunology Training Grant, The University of Chicago, 5T32AI007090 to A.Z., F.J.K. and J.A.O.; and the Cancer Research Foundation (Young Investigator Award) to J.A.G.-P.