Th22 cells are a major contributor to the mycobacterial CD4+ T cell response and are depleted during HIV infection

Abstract

41HIV-1 infection substantially increases the risk of developing tuberculosis (TB). Some 42 mechanisms, such as defects in the Th1 response to Mycobacterium tuberculosis (M.tb) in 43HIV-infected individuals have been widely reported. However, Th1-independent mechanisms 44 also contribute to protection against TB. To identify a broader spectrum of defects in TB 45 immunity during HIV infection, we examined IL-17 and IL-22 production in response to 46 mycobacterial antigens in individuals with latent TB infection (LTBI) and HIV co-infection. 47Upon stimulating with mycobacterial antigens, we observed a distinct CD4+ T helper lineage 48 producing IL-22 in the absence of IL-17 and IFN-γ. Th22 cells were present at high 49 frequencies in response to mycobacterial antigens in blood and contributed up to 50% to the 50 CD4+ T cell response to mycobacteria, comparable in magnitude to the IFN-γ Th1 response 51 (median 0.91% and 0.55%, respectively). Phenotypic characterization of Th22 cells revealed 52 that their memory differentiation was similar to M.tb-specific Th1 cells (i.e. predominantly 53 early-differentiated CD45RO+CD27+ phenotype). Moreover, CCR6 and CXCR3 expression 54 profiles of Th22 cells were similar to Th17 cells, while their CCR4 and CCR10 expression 55 patterns displayed an intermediate phenotype between Th1 and Th17 cells. Strikingly, 56 mycobacterial IL-22 responses were three-fold lower in HIV-infected individuals compared 57 to uninfected individuals, and the magnitude of responses correlated inversely with HIV viral 58 load. These data provide important insights into mycobacteria-specific T helper subsets and 59 suggest a potential role for IL-22 in protection against TB during HIV infection. Further 60 studies are needed to fully elucidate the role of IL-22 in protective TB immunity. 61 4 INTRODUCTION 62

Characterization of Mycobacterium tuberculosis-specific Th22 cells and the effect of tuberculosis disease and HIV co-infection

“…IL-22 has been classified as a Th17 cytokine due to co-expression with IL-17 in mouse studies and several shared functions between the two cytokines (39). Consistent with previous studies (29,31), our results showed that the vast majority of IL-22 is produced independently of IL- In accordance with previous data (25), we show that Mtb-specific Th22 responses in the blood were 50% lower in individuals with TB compared to Mtb-exposed individuals. It is likely that in the context of TB disease, Mtb-specific Th22 cells migrate to the lungs.…”

“…A subset of CD4+ T cells that produces the cytokine IL-22 in response to mycobacterial antigen stimulation has been described (29)(30)(31). We sought to further characterize Mtb-specific IL- repertoire coverage for Mtb-specific IL-22-producing CD4+ T cells was broad and comparable to total CD4+ T cells, while slightly lower coverage was observed for Mtb-specific IFN- producing CD4+ T cells (medians 62%, 61% and 40%, respectively).…”

“…Consistent with our recent findings (31), HIV infection resulted in a lower frequency of Th1 and Th22 cells in Mtb-exposed individuals, and also those with active TB. The depletion of Th22 cells could be explained by the fact that the majority of Th22 cells express CCR6 (31), and CD4+ CCR6+ cells display an increased permissiveness to HIV infection (47)(48)(49), are enriched in HIV DNA (50), and appear to preferentially support HIV replication (51). Indeed, CD4+CCR6+ cells have been shown to express high levels of the HIV co-receptors CCR5 and CXCR4, important for viral entry, as well as integrin 47, which has been associated with increased HIV susceptibility (47,48,52).…”

Multidimensional analyses reveal modulation of adaptive and innate immune subsets by tuberculosis vaccines

“…In non-human primates, IL-22 mRNA expression was reduced in peripheral blood of Mtb-infected monkeys but increased in lung lymphocytes, bronchial lymph nodes, and spleen, suggesting a role for IL-22 in lymphoid and lung tissues 60 . Finally, several studies have reported IL-22 expression after BCG stimulation of whole blood from individuals living in settings endemic for TB 46,[61][62][63] . Interestingly, IL-22-expressing cells are not readily detected after stimulation of PBMC or in response to peptides 61 .…”

“…Finally, several studies have reported IL-22 expression after BCG stimulation of whole blood from individuals living in settings endemic for TB 46,[61][62][63] . Interestingly, IL-22-expressing cells are not readily detected after stimulation of PBMC or in response to peptides 61 . This technical observation has important implications for studies that seek to determine if IL-22 is a correlate of protection, since such studies are typically done on cryopreserved PBMC.…”