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Antigen-specific CD4+ T cells promote monocyte recruitment and differentiation into glycolytic lung macrophages to control Mycobacterium tuberculosis.

ABSTRACT: Although lung myeloid cells provide an intracellular niche for Mycobacterium tuberculosis (Mtb), CD4+ T cells limit Mtb growth in these cells to protect the host. Here, we show that monocyte-derived macrophages (MDMs), instead of phenotypically similar dendritic cells, are preferentially infected with Mtb in murine lungs. Mtb-specific CD4+ T cells recruited monocyte precursors of MDMs into the lungs via interferon-γ (IFN-γ). Although the CD4+ T cells increased the number of Mtb-infectable cells in the lungs, they then attenuated Mtb growth by engaging in MHC class II (MHCII)-mediated cognate interactions with monocyte-derived cells to promote their disinfection. Specifically, cognate CD4+ T cell help via MHCII enhanced MDM expression of glycolytic genes independently of IFN-γ. These results indicate that CD4+ T cells recruit infectable MDMs to the lungs and trigger glycolysis-dependent bacterial control within them by engaging MHCII-bound Mtb peptides on their surfaces.

ORGANISM(S): Mus musculus

PROVIDER: GSE287753 | GEO | 2025/01/27

REPOSITORIES: GEO

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Project description:Innate memory phenotype (IMP) CD4+ T cells are non-conventional Î±Î² T cells exhibiting features of innate immune cells, characterized as CD44high and CD62Llow in periphery. It is recently reported by our group that bone marrow chimeric mice lacking thymic MHCI expression develop predominantly IMP CD8+ T cells, while those lacking hematopoietic MHCI develop predominantly naÃ¯ve CD8+ T cells. Here we perform hirarchical clustering analysis and found that CD4+ T cells share similar property: chimeras lacking thymic MHCII gave rise to predominantly CD4+ T cells that resemble IMP CD4+ T cells observed in WT mice, and vice versa, chimeras lacking hematopoietic MHCII had a majority of naÃ¯ve-like CD4+ T cells resembling naÃ¯veCD4+ T cells seen in WT mice. We used microarrays to compare the global programme of gene expression to determine whether the hematopoietic MHCII selected CD4+ T cells are IMP, and whether the thymic MHCII selected CD4+ T cells are naÃ¯ve CD4+ T cells as observed in WT mice. Through hierarchical clustering and analysis of global gene differential expression, we determined that hematopoietic MHCII dependent IMP CD4+ T cells generated from WT bone marrow transplanted into irradiated MHCII-/- recipients, resemble IMP CD4+ T cells in WT mice, while naÃ¯ve CD4+ T cells generated from MHCII-/- bone marrow transplanted into irradiated WT recipients, resemble naÃ¯ve CD4+ T cells in WT mice. Cell Sorting was performed using a Cytopeia Influx Cell Sorter. Chimeric IMP (CD45.1+TCRÎ²+CD4+CD44highCD62Llow) CD4+ T cells were sorted from splenocytes of CD45.1+WTâCD45.2+MHCII-/- chimeras (WM IMP CD4), and chimeric naÃ¯ve (CD45.2+TCRÎ²+CD4+CD44lowCD62Lhigh) CD4+ T cells were sorted from splenocytes of CD45.2+MHCII-/- â CD45.1+WT chimeras (MW naÃ¯ve CD4) respectively, 8 weeks post transplantation. WT IMP (TCRÎ²+CD4+CD44highCD62Llow) and naÃ¯ve (TCRÎ²+CD4+CD44lowCD62Lhigh) CD4+ T cells were sorted from splenocytes of 8-week old WT mice.