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CD4⁺ T cells are homeostatic regulators during Mtb reinfection.

ABSTRACT: Immunological priming - either in the context of prior infection or vaccination - elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Here, using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrate that prior Mtb infection elicits a long-lasting protective response against subsequent Mtb exposure and that the depletion of CD4⁺ T cells prior to Mtb rechallenge significantly abrogates this protection. Leveraging microbiologic, PET-CT, flow cytometric, and single-cell RNA-seq data from primary infection, reinfection, and reinfection-CD4⁺ T cell depleted granulomas, we identify differential cellular and microbial features of control. The data collectively demonstrate that the presence of CD4⁺ T cells in the setting of reinfection results in a reduced inflammatory lung milieu characterized by reprogrammed CD8⁺ T cell activity, reduced neutrophilia, and blunted type-1 immune signaling among myeloid cells, mitigating Mtb disease severity. These results open avenues for developing vaccines and therapeutics that not only target CD4⁺ and CD8⁺ T cells, but also modulate innate immune cells to limit Mtb disease.

SUBMITTER: Bromley JD

PROVIDER: S-EPMC10769325 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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CD4+ T cells are homeostatic regulators during Mtb reinfection.

Bromley Joshua D JD Ganchua Sharie Keanne C SKC Nyquist Sarah K SK Maiello Pauline P Chao Michael M Borish H Jacob HJ Rodgers Mark M Tomko Jaime J Kracinovsky Kara K Mugahid Douaa D Nguyen Son S Wang Dennis D Rosenberg Jacob M JM Klein Edwin C EC Gideon Hannah P HP Floyd-O'Sullivan Roisin R Berger Bonnie B Scanga Charles A CA Lin Philana Ling PL Fortune Sarah M SM Shalek Alex K AK Flynn JoAnne L JL

bioRxiv : the preprint server for biology 20231221

Immunological priming - either in the context of prior infection or vaccination - elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Here, using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrate that prior Mtb infecti ...[more]

PMID: 38187598

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Project description:BackgroundEffector CD4 T cells represent a key component of the host's anti-tuberculosis immune defense. Successful differentiation and functioning of effector lymphocytes protects the host against severe M. tuberculosis (Mtb) infection. On the other hand, effector T cell differentiation depends on disease severity/activity, as T cell responses are driven by antigenic and inflammatory stimuli released during infection. Thus, tuberculosis (TB) progression and the degree of effector CD4 T cell differentiation are interrelated, but the relationships are complex and not well understood. We have analyzed an association between the degree of Mtb-specific CD4 T cell differentiation and severity/activity of pulmonary TB infection.Methodology/principal findingsThe degree of CD4 T cell differentiation was assessed by measuring the percentages of highly differentiated CD27(low) cells within a population of Mtb- specific CD4 T lymphocytes ("CD27(low)IFN-?(+)" cells). The percentages of CD27(low)IFN-?+ cells were low in healthy donors (median, 33.1%) and TB contacts (21.8%) but increased in TB patients (47.3%, p<0.0005). Within the group of patients, the percentages of CD27(low)IFN-?(+) cells were uniformly high in the lungs (>76%), but varied in blood (12-92%). The major correlate for the accumulation of CD27(low)IFN-?(+) cells in blood was lung destruction (r = 0.65, p = 2.7 × 10(-7)). A cutoff of 47% of CD27(low)IFN-?(+) cells discriminated patients with high and low degree of lung destruction (sensitivity 89%, specificity 74%); a decline in CD27(low)IFN-?(+)cells following TB therapy correlated with repair and/or reduction of lung destruction (p<0.01).ConclusionsHighly differentiated CD27(low) Mtb-specific (CD27(low)IFN-?(+)) CD4 T cells accumulate in the lungs and circulate in the blood of patients with active pulmonary TB. Accumulation of CD27(low)IFN-?(+) cells in the blood is associated with lung destruction. The findings indicate that there is no deficiency in CD4 T cell differentiation during TB; evaluation of CD27(low)IFN-?(+) cells provides a valuable means to assess TB activity, lung destruction, and tissue repair following TB therapy.

Project description:While liver inflammation is associated with AIDS, little is known so far about hepatic CD4+ T cells. By using the simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) model, we aimed to characterize CD4+ T cells. The phenotype of CD4+ T cells was assessed by flow cytometry from uninfected (n = 3) and infected RMs, with either SIVmac251 (n = 6) or SHIVSF162p3 (n = 6). After cell sorting of hepatic CD4+ T cells, viral DNA quantification and RNA sequencing were performed.Thus, we demonstrated that liver CD4+ T cells strongly expressed the SIV coreceptor, CCR5. We showed that viremia was negatively correlated with the percentage of hepatic effector memory CD4+ T cells. Consistent with viral sensing, inflammatory and interferon gene transcripts were increased. We also highlighted the presence of harmful CD4+ T cells expressing GZMA and members of TGFB that could contribute to fuel inflammation and fibrosis. Whereas RNA sequencing demonstrated activated CD4+ T cells displaying higher levels of mitoribosome and membrane lipid synthesis transcripts, few genes were related to glycolysis and oxidative phosphorylation, which are essential to sustain activated T cells. Furthermore, we observed lower levels of mitochondrial DNA and higher levels of genes associated with damaged organelles (reticulophagy and mitophagy). Altogether, our data revealed that activated hepatic CD4+ T cells are reprogrammed to lipid metabolism. Thus, strategies aiming to reprogram T cell metabolism with effector function could be of interest for controlling viral infection and preventing liver disorders.IMPORTANCEHuman immunodeficiency virus (HIV) infection may cause liver diseases, associated with inflammation and tissue injury, contributing to comorbidity in people living with HIV. Paradoxically, the contribution of hepatic CD4+ T cells remains largely underestimated. Herein, we used the model of simian immunodeficiency virus (SIV)-infected rhesus macaques to access liver tissue. Our work demonstrates that hepatic CD4+ T cells express CCR5, the main viral coreceptor, and are infected. Viral infection is associated with the presence of inflamed and activated hepatic CD4+ T cells expressing cytotoxic molecules. Furthermore, hepatic CD4+ T cells are reprogrammed toward lipid metabolism after SIV infection. Altogether, our findings shed new light on hepatic CD4+ T cell profile that could contribute to liver injury following viral infection.

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CD4⁺ T cells are homeostatic regulators during Mtb reinfection.

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CD4<sup>+</sup> T cells are homeostatic regulators during <i>Mtb</i> reinfection.

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