Aberrant adaptive immune response underlies genetic susceptibility to tuberculosis

( ) remains a major threat worldwide, although only a fraction of infected individuals develops tuberculosis (TB). TB susceptibility is shaped by multiple genetic factors, and we performed comparative immunological analysis of two mouse strains to uncover relevant mechanisms underlying susceptibilit...

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Published in:	Frontiers in immunology Vol. 15; p. 1380971
Main Authors:	Tsareva, Anastasiia, Shelyakin, Pavel V, Shagina, Irina A, Myshkin, Mikhail Yu, Merzlyak, Ekaterina M, Kriukova, Valeriia V, Apt, Alexander S, Linge, Irina A, Chudakov, Dmitriy M, Britanova, Olga V
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 2024
Subjects:	Adaptive Immunity - genetics Animals B cells B-Lymphocytes - immunology CD4 + T cells Disease Models, Animal Genetic Predisposition to Disease immunoglobulins Lung - immunology Lung - pathology Mice Mice, Inbred C57BL Mycobacterium tuberculosis - immunology Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - immunology TB-susceptible mouse strain TCR repertoire tuberculosis Tuberculosis - genetics Tuberculosis - immunology transcriptomic signatures tuberculosis CD4 + T cells B cells immunoglobulins TCR repertoire TB-susceptible mouse strain
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Summary:	( ) remains a major threat worldwide, although only a fraction of infected individuals develops tuberculosis (TB). TB susceptibility is shaped by multiple genetic factors, and we performed comparative immunological analysis of two mouse strains to uncover relevant mechanisms underlying susceptibility and resistance. C57BL/6 mice are relatively TB-resistant, whereas I/St mice are prone to develop severe TB, partly due to the MHC-II allelic variant that shapes suboptimal CD4 T cell receptor repertoire. We investigated the repertoires of lung-infiltrating helper T cells and B cells at the progressed stage in both strains. We found that lung CD4 T cell repertoires of infected C57BL/6 but not I/St mice contained convergent TCR clusters with functionally confirmed specificity. Transcriptomic analysis revealed a more prominent Th1 signature in C57BL/6, and expression of pro-inflammatory IL-16 in I/St lung-infiltrating helper T cells. The two strains also showed distinct Th2 signatures. Furthermore, the humoral response of I/St mice was delayed, less focused, and dominated by IgG/IgM isotypes, whereas C57BL/6 mice generated more antigen-focused IgA response. We conclude that the inability of I/St mice to produce a timely and efficient anti- adaptive immune responses arises from a suboptimal helper T cell landscape that also impacts the humoral response, leading to diffuse inflammation and severe disease.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2024.1380971