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: ESAT-6–specific T cells in the lung can be separated into two distinct populations based on their expression of the inhibitory receptors PD-1 and KLRG1 (Fig. 3 A). Consistent with the findings of a recent report (Reiley et al., 2010), we found that KLRG1+ cells produced more IFN-γ and TNF than their PD-1+ KLRG1− counterparts after in vitro stimulation with ESAT-6 peptide or anti-CD3 and anti-CD28 antibodies (unpublished data). In contrast, KLRG1+ cells produced very little IL-2, a cytokine almost exclusively produced by a population of polyfunctional PD-1+ KLRG1− cells that also produced IFN-γ and TNF (Fig. 3 B and not depicted). No TNF or IL-2 staining was detected in lung T cells using the direct ex vivo approach. However, consistent with the in vitro restimulation data, a higher percentage of KLRG1+ than PD-1+ KLRG1− CD4 T cells within the tetramer-binding population produced IFN-γ when assessed immediately after isolation from the lung (Fig. 3 C). Furthermore, KLRG1+ cells expressed high levels of the Th1-defining transcription factor T-bet, whereas PD-1+KLRG1− cells had intermediate T-bet levels (Fig. 3 D). We also found that PD-1+KLRG1− ESAT-6–specific CD4 T cells exhibited more proliferation (assessed by Ki67 expression) than KLRG1+ cells at time points beyond day 28 after infection (Fig. 3 E). Overall, these results indicate KLRG1+ cells comprise the primary ESAT-6–specific CD4 T cell population producing IFN-γ in vivo, but PD-1+ cells have a higher capacity to produce IL-2 and undergo more extensive proliferation.
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.