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: The chemokine receptor CXCR5 is regulated by Bcl6 (Choi et al., 2011) and intrinsic expression of CXCR5 by CD4 T cells plays an important role in TB immunity (Slight et al., 2013). To address the role of CXCR5 in Mtb-specific CD4 T cells, we generated WT plus CXCR5−/− mixed bone marrow chimeras. Immediately before Mtb infection, reconstituted chimeras showed a 1:1 ratio of WT: CXCR5−/− CD4 T cells in their blood, and this ratio remained at 1:1 for naive T cells isolated from the lung, even at day 119 after infection (Fig. 10 A). In contrast to our findings in Bcl6 chimeras, similar numbers of CXCR5−/− and WT ESAT-6 tetramer-binding CD4 T cells were observed during early infection, but CXCR5−/− cells showed diminished persistence after 120 d after infection (Fig. 10 B). Unlike the phenotypic and functional differences observed in Bcl-6–deficient T cells (Fig. 9); however, CXCR5-deficient and WT T cells showed similar PD-1/KLRG1 profiles, distribution between the lung parenchymal/intravascular compartments, levels of T-bet expression, and direct ex vivo IFN-γ production (unpublished data). Thus, although intrinsic CXCR5 expression is required to maintain Mtb-specific CD4 T cells during chronic infection, the function of CXCR5 only accounts for a small part of the observed function of Bcl6.
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.