Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

Abstract

27Mycobacterium tuberculosis (Mtb)-specific T cell responses associated with immune control 28 during asymptomatic latent tuberculosis infection (LTBI) remain poorly understood. Using a non-29 human primate (NHP) aerosol model, we studied the kinetics, phenotypes and functions of Mtb 30 antigen-specific T cells in peripheral and lung compartments of Mtb-infected asymptomatic 31 rhesus macaques by longitudinally sampling blood and bronchoalveolar lavage (BAL), for up to 32 24 weeks post-infection. We found significantly higher frequencies of Mtb-specific effector and 33 memory CD4 and CD8 T cells producing IFN-γ in the airways compared to peripheral blood, 34 which were maintained throughout the study period. Moreover, Mtb-specific IL-17+ and IL-35 17/IFN-γ double-positive T cells were present in the airways but were largely absent in the 36 periphery, suggesting that balanced mucosal Th 1 /Th 17 responses are associated with LTBI. The 37 majority of Mtb-specific CD4 T cells that homed to the airways expressed the chemokine 38 receptor CXCR3 and co-expressed CCR6. Notably, CXCR3+CD4+ cells were found in 39 granulomatous and non-granulomatous regions of the lung and inversely correlated with Mtb 40 burden. Our findings provide novel insights into antigen-specific T cell responses associated 41 with asymptomatic Mtb infection that are relevant for developing better strategies to control TB. 42 43 46 51 (LTBI)(1). Individuals with LTBI are defined as having a positive tuberculin skin test (TST) 52 and/or Interferon-gamma Release Assay (IGRA), a normal chest radiograph and the absence of 53 clinical signs and symptoms of disease(2). Latently-infected individuals are generally thought to 54 contain Mtb within granulomatous lesions in the lung without completely eradicating bacteria, 55 although direct evidence for the persistence of Mtb in human LTBI is lacking. Moreover, it is 56 increasingly recognized that clinically asymptomatic individuals likely reflect a spectrum of 57 infection outcomes, ranging from individuals who may have eliminated infection, to those with 58 low levels of replicating or non-replicating persistent bacteria, to individuals who may harbor 59 actively replicating bacteria without exhibiting overt clinical symptoms(3-5). Identifying immune 60 responses associated with asymptomatic Mtb infection states will provide key insights into 61 mechanisms of immune control that protect against progressing to active TB disease. 62 63 Antigen-specific T cell responses are critical for immune control of Mtb infection. In response to 64 Mtb infection, the majority of infected people mount robust CD4 T cell responses involving T 65 helper 1 (Th 1 ) cytokines such as IFN-γ and TNF-α, which are important for activating 66 macrophages and curtailing Mtb replication in the lung(6, 7). In addition, IL-17 and Th 17 67 responses have emerged as important for protective immunity against TB, but mucosal Mtb-68 specific Th 17 responses during immune control of LTBI in humans remain poorly studied. In 69 general, the na...

Multimodally profiling memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment and disease

“…Previous studies in latent infection have mapped the bulk of M.tb antigen-specific cells to a Th1/17 CCR6+CXCR3+ state (distinct from C-12) that is expanded in latent compared to uninfected individuals 29 , 65 . Although these cells produced only IFNγ upon ex vivo M.tb antigen stimulation in those studies, in non-human primates they also produce IL-17 in bronchoalveolar lavage and expand in the lungs during latent infection compared to TB disease 66 and upon intravenous Bacillus Calmette-Gueérin (BCG) vaccination 67 . IL-17 and IL-22 production and other aspects of the C-12 phenotype have also been previously identified in M.tb antigen-specific cells during active TB disease 14 , 15 , 43 .…”

Complement activation induces excessive T cell cytotoxicity in severe COVID-19

“…This clearly distinguished them from the other CD16 lo T cell clusters e.g. cluster 18 and promoting migration into the lungs (Oja et al, 2018;Shanmugasundaram et al, 2020). Indeed, BAL samples from COVD-19 compared to control pneumonia showed an enrichment of FCGR3A + T cells with high cytotoxic and degranulation potential (Figure 4G-J).…”

Multimodal memory T cell profiling identifies a reduction in a polyfunctional Th17 state associated with tuberculosis progression

“…Although studies have emphasized that CCR6+CXCR3+ cells produce IFNγ upon M.tb antigen stimulation, in non-human primates this cell state also produces IL-17 in bronchoalveolar lavage and is expanded in the lungs during latent infection compared to TB disease 53 . Second, mutations in RORC-the Th17 lineage-defining transcription factor that is highly expressed in C-12-increase susceptibility to mycobacterial diseases 5 .…”