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: To determine whether PD-1+ cells had the capacity to mount a recall response, we challenged mice (with aerosolized Mtb) that had received equal numbers of ESAT-6–specific donor PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells 10 d before. At 28 d after infection, we found that donor cells derived from PD-1+ precursors had undergone robust expansion, whereas KLRG1+ precursors had not (Fig. 6 A). Furthermore, PD-1+ progenitors had the capacity to differentiate into KLRG1+ cells in response to Mtb challenge. In fact, the profile of PD-1 vs. KLRG1 expression for ESAT-6–specific CD4 T cells derived from transferred PD-1+ cells was nearly identical to that for endogenous tetramer-binding CD4 T cells participating in the primary response to Mtb. Conversely, most of the tetramer-binding cells derived from transferred KLRG1+ cells retained a KLRG1+ phenotype (Fig. 6 B). Overall, despite being subjected to chronic antigenic stimulation and exhibiting some phenotypic markers of effector T cells, lung-resident, Mtb-specific, PD-1+ CD4 T cells share many features with classically defined memory T cells. Like memory T cells, they can persist in the absence of antigen and mount a robust recall response that generates a heterogeneous population of cells resembling the cells responding to a primary infection (Marshall et al., 2011; Pepper et al., 2011; Hale et al., 2013).
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.