Direct in vivo evidence of CD4+ T cell requirement for CTL response and memory via pMHC-I targeting and CD40L signaling

Journal of Leukocyte Biology

Philip Griebel– and¹  John R. Gordon¹  Jim Xiang, ¹  Sean J. Mulligan¹  Khawaja Ashfaque Ahmed, ¹  Manjunatha Ankathatti Munegowda¹  Lu Wang, ¹ 

[1] Research Unit, Saskatchewan Cancer Agency, Departments of  Oncology and Physiology and Division of Respirology, Critical Care and Sleep Medicine, –Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan Canada

关键词: dendritic cells;    antigen presentation;    immune response;    adaptive immunity;   

DOI  :  10.1189/jlb.1211631

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

CD4+ T cell help contributes critically to DC-induced CD8+ CTL immunity. However, precisely how these three cell populations interact and how CD4+ T cell signals are delivered to CD8+ T cells in vivo have been unclear. In this study, we developed a novel, two-step approach, wherein CD4+ T cells and antigen-presenting DCs productively engaged one another in vivo in the absence of cognate CD8+ T cells, after which, we selectively depleted the previously engaged CD4+ T cells or DCs before allowing interactions of either population alone with naïve CD8+ T cells. This protocol thus allows us to clearly document the importance of CD4+ T-licensed DCs and DC-primed CD4+ T cells in CTL immunity. Here, we provide direct in vivo evidence that primed CD4+ T cells or licensed DCs can stimulate CTL response and memory, independent of DC-CD4+ T cell clusters. Our results suggest that primed CD4+ T cells with acquired pMHC-I from DCs represent crucial “immune intermediates” for rapid induction of CTL responses and for functional memory via CD40L signaling. Importantly, intravital, two-photon microscopy elegantly provide unequivocal in vivo evidence for direct CD4-CD8+ T cell interactions via pMHC-I engagement. This study corroborates the coexistence of direct and indirect mechanisms of T cell help for a CTL response in noninflammatory situations. These data suggest a new “dynamic model of three-cell interactions” for CTL immunity derived from stimulation by dissociated, licensed DCs, primed CD4+ T cells, and DC-CD4+ T cell clusters and may have significant implications for autoimmunity and vaccine design.

【 授权许可】

Unknown