ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis.
Bottom Line: When transferred into uninfected animals, these cells persist, mount a robust recall response, and provide superior protection to Mtb rechallenge when compared to terminally differentiated Th1 cells that reside preferentially in the lung-associated vasculature.Thus, the molecular pathways required to maintain Mtb-specific CD4 T cells during ongoing infection are similar to those that maintain memory CD4 T cells in scenarios of antigen deprivation.These results suggest that vaccination strategies targeting the ICOS and Bcl6 pathways in CD4 T cells may provide new avenues to prevent TB.
Affiliation: Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104.Show MeSH
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Mentions: Although PD-1+ Mtb-specific CD4 T cells have Tfh-like features, further analysis of cell surface and intracellular molecules revealed a mixed profile, with expression of both effector and memory markers (Fig. 5 A). CD62L expression reflected an effector phenotype and was low in both PD-1+KLRG1− and PD-1−KLRG1+ tetramer-binding populations. Although CCR7 and CD127 expression was slightly higher among PD-1+KLRG1− compared with PD-1−KLRG1+ cells, this expression did not approach the levels usually observed on central memory cells that develop when antigen is cleared. In contrast, as we had previously observed for ICOS and CD69 (Fig. 4 A), CXCR3, Ly6C, and CD43 showed markedly distinct expression patterns on these two populations (Fig. 5 A). Most ESAT-6–specific PD-1+KLRG1− cells were CXCR3+, Ly6C−, and CD43+, whereas most PD-1−KLRG1+ cells exhibited the opposite phenotype. In addition, PD-1+KLRG1− cells, like memory cells (Marshall et al., 2011), were intermediate for T-bet expression, whereas PD-1−KLRG1+ cells, like Th1 effector cells, exhibited high T-bet expression (Fig. 3 D). Our results reveal that ESAT-6–specific PD-1+ CD4 T cells, while expressing some markers of effector T cells, also displayed features of memory T cells. In contrast, their KLRG1+ counterparts exhibit characteristics of terminally differentiated effector Th1 cells.
Affiliation: Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104.