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. 2018 Feb 27;115(9):2168-2173.
doi: 10.1073/pnas.1716146115. Epub 2018 Feb 12.

Sex bias in MHC I-associated shaping of the adaptive immune system

Tilman Schneider-Hohendorf  1 , Dennis Görlich  2 , Paula Savola  3 , Tiina Kelkka  3 , Satu Mustjoki  3 , Catharina C Gross  1 , Geoffrey C Owens  4 , Luisa Klotz  1 , Klaus Dornmair  5 , Heinz Wiendl  1 , Nicholas Schwab  6
Affiliations

Sex bias in MHC I-associated shaping of the adaptive immune system

Tilman Schneider-Hohendorf et al. Proc Natl Acad Sci U S A. .

Abstract

HLA associations, T cell receptor (TCR) repertoire bias, and sex bias have independently been shown for many diseases. While some immunological differences between the sexes have been described, they do not fully explain bias in men toward many infections/cancers, and toward women in autoimmunity. Next-generation TCR variable beta chain (TCRBV) immunosequencing of 824 individuals was evaluated in a multiparametric analysis including HLA-A -B/MHC class I background, TCRBV usage, sex, age, ethnicity, and TCRBV selection/expansion dynamics. We found that HLA-associated shaping of TCRBV usage differed between the sexes. Furthermore, certain TCRBVs were selected and expanded in unison. Correlations between these TCRBV relationships and biochemical similarities in HLA-binding positions were different in CD8 T cells of patients with autoimmune diseases (multiple sclerosis and rheumatoid arthritis) compared with healthy controls. Within patients, men showed higher TCRBV relationship Spearman's rhos in relation to HLA-binding position similarities compared with women. In line with this, CD8 T cells of men with autoimmune diseases also showed higher degrees of TCRBV perturbation compared with women. Concerted selection and expansion of CD8 T cells in patients with autoimmune diseases, but especially in men, appears to be less dependent on high HLA-binding similarity than in CD4 T cells. These findings are consistent with studies attributing autoimmunity to processes of epitope spreading and expansion of low-avidity T cell clones and may have further implications for the interpretation of pathogenic mechanisms of infectious and autoimmune diseases with known HLA associations. Reanalysis of some HLA association studies, separating the data by sex, could be informative.

Keywords: T cell receptor repertoire; autoimmunity; immunological sex bias; multiple sclerosis; rheumatoid arthritis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Sex bias in HLA-associated shaping of the TCRBV usage. Shown are uncorrected P values from a multivariate linear regression model (covariates in Dataset S2), assessing the interaction of HLA and sex on TCRBV usage. HLA/TCRBV combinations highlighted in red indicate P < 0.05 after Bonferroni correction for multiple comparisons; yellow color suggests additional, potentially sex-specific HLA/TCRBV combinations, which did not pass Bonferroni correction. Left columns indicate the total number (N) as well as the male (M) and female (F) subject numbers for each HLA (raw data in Dataset S3), and green color indicates that this inclusion criterion was passed (one criterion was enough for inclusion).
Fig. 2.
Fig. 2.
CD8 T cells in men with autoimmune diseases are less dependent on biochemical CDR1/2 similarity for concerted selection/expansion. (A) TCRBV relationships Spearman’s correlation coefficients (TCRBV rhos) of CD4 T cells of healthy donors (HD) and MS patients grouped according to BLOSUM-low and BLOSUM-high scores and divided by sex [male (red) versus female (blue)]. Shown are mean and 95% confidence interval. (B) Parameters of the linear model for CD4 T cells. Shown are the type III sum of squares (type III SS), degrees of freedom (df), mean square (mean squ.), F score, significance (P value), and partial eta squared (ɳp2) as effect size. (C) TCRBV rhos of CD8 T cells of healthy donors (HD), and MS and RA patients grouped according to A. (D) Parameters of the linear model for CD8 T cells according to B. Two nested models are shown (BLOSUM-low and BLOSUM-high) within CD8 T cells. Pairwise comparison (superscript a) of the mean is shown for groups of interest (Bonferroni-corrected Student’s t test). (E) TCRBV perturbation, measured as productive clonality. Shown are paired comparisons (Wilcoxon matched pairs signed rank test) between age-matched male and female individuals (CD4 and CD8 T cells; HD, MS, or RA).
Fig. 3.
Fig. 3.
In vivo relationships between TCRBV chains are similar in naïve and memory T cell subsets. (A) TCRBV perturbation quantified by the sequencing parameter productive clonality of naïve and memory CD4 and CD8 T cell subsets from 25 healthy subjects. (B) TCRBV rhos of naïve (red) and memory (blue) CD4/CD8 T cells grouped according to low and high BLOSUM scores. Shown is mean and 95% confidence interval (TCRBV rhos in Dataset S5 and raw data in Dataset S7). (C) Parameters of the linear model with TCRBV rhos as dependent and cell type, maturation, BLOSUM scores as main effects with the added interaction of those three main effects.
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