Polygenic TB control and the sequence of innate/adaptive immune responses to infection: MHC-II alleles determine the size of the S100A8/9-producing neutrophil population.

Autor: Logunova N; Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia., Kapina M; Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia., Dyatlov A; Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia., Kondratieva T; Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia., Rubakova E; Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia., Majorov K; Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia., Kondratieva E; Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia., Linge I; Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia., Apt A; Laboratory for Immunogenetics, Central Tuberculosis Research Institute, Moscow, Russia.
Jazyk: angličtina
Zdroj: Immunology [Immunology] 2024 Oct; Vol. 173 (2), pp. 381-393. Date of Electronic Publication: 2024 Jul 14.
DOI: 10.1111/imm.13836
Abstrakt: Among several quantitative trait loci involved in tuberculosis (TB) control in mice, one was mapped within the chromosome 17 segment occupied by the H2 complex and another within the chromosome 3 segment comprising the S100A8/9 genes, which encode neutrophil inflammatory factor S100A8/9. Previously, we developed a panel of H2-congenic mouse strains differing by small segments of the major histocompatibility complex Class II (MHC-II) region from TB-susceptible H2 j mice transferred onto the genetic background of the TB-resistant C57BL/6 (H2 b ) strain. Susceptible B6.I-9.3 mice differ from B6 progenitors by the alleles of their only classical MHC-II H2-Aβ gene. The goals of the present study were to: (i) comprehensively characterise the differences in TB-related phenotypes between mice of the two strains and (ii) decipher interactions between the H2-Aβ and S100A8/9 genes. Here, we describe the dynamics of TB-related phenotypes differentiating B6.I-9.3 and B6 mice (colony forming units counts, histopathology, lung immune cell infiltration and cytokine profiles). We show that disproportionally diminished CD4 + T-cell population, an enlarged S100A8/9-positive neutrophil population and higher S100A8/9 serum levels in B6.I-9.3 mice collectively form the 'susceptible' phenotype before infection. An increase in IL-17 and a decrease in intrferon-gamma production by CD4 + T-cells in these mice provide a mechanistic explanation of this phenotype. Using F2 segregation analysis, we show that the number of S100A8/9-producing neutrophils in lungs and spleens and the proportion of Th17 CD4 + T-cells in lungs are significantly lower in the presence of the MHC-II dominant 'resistant' b allele compared to the recessive 'susceptible' j/j genotype. This provides direct genetic evidence that MHC-II-regulated CD4 + T-cell landscapes determine neutrophil abundance before infection, an important pathogenic factor in TB immunity.
(© 2024 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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