Biology subjects

Gittelman, R. M.

Publications and source records attributed to Gittelman, R. M..

2 recordsLinked to original sources

bioRxiv2024

Antigen-driven expansion of public clonal T cell populations in inflammatory bowel diseases

BackgroundInflammatory Bowel Diseases (IBDs), including Crohns disease (CD) and ulcerative colitis (UC), are known to involve shifts in the T-cell repertoires of affected individuals. These include a reduction in regulatory T cells in both diseases, increase in TNF production in CD, expansion of an unconventional T-cell population in CD, and clonal expansion of abundant T-cell populations in CD mucosal tissue. There are also differential HLA risk and protective alleles between CD and UC, implying CD- and UC-specific repertoire changes that have not yet been identified. MethodsWe performed ImmunoSequencing on blood samples from 3,853 CD cases, 1,803 UC cases, and 5,596 healthy controls. For each sample we imputed HLA type and cytomegalovirus (CMV) infection status based on public T-cell receptor {beta} (TCRB) usage and identified public TCRBs enriched in CD or UC cases. FindingsWe determine that there is more expansion across clonotypes in CD, but not UC, compared with healthy controls. We also identify novel interactive effects of HLA-DQ heterodimers with CD and UC risk. Strikingly, from blood we identify public TCRBs specifically expanded in CD or UC. These sequences are more abundant in intestinal mucosal samples, form groups of similar CDR3 sequences, and can be associated to specific HLA alleles. Although the prevalence of these sequences is higher in ileal and ileocolonic CD than colonic CD or UC, the TCRB sequences themselves are shared across CD and not between CD and UC. InterpretationThere are peptide antigens that commonly evoke immune reactions in IBD cases and rarely in non-IBD controls. These antigens differ between CD and UC. CD, particularly ileal CD, also seems to involve more substantial changes in clonal population structure than UC, compared to healthy controls.

immunology↗

bioRxiv2021

HLA Type and Chronic Viral Infection Impact Peripheral T-cell Receptor Sharing Between Unrelated Individuals

The human adaptive immune system must generate extraordinary diversity to be able to respond to all possible pathogens. The T-cell repertoire derives this high diversity through somatic recombination of the T-cell receptor (TCR) locus, a random process that results in repertoires that are largely private to each individual. However, certain factors such as low junctional diversity, thymic selection, and T-cell proliferation upon antigen exposure can affect TCR sharing among individuals. By immunosequencing the TCR{beta} variable region of 426 healthy individuals, we find that fewer than 1% of TCR{beta} clones are shared between individuals on average, consistent with largely private TCR{beta} repertoires. However, we detect a significant correlation between increased HLA allele sharing and increased number of shared TCR{beta} clones, with each additional shared HLA allele contributing to an increase in [~]0.01% of the total TCR{beta} clones being shared, supporting a key role for HLA type in shaping the immune repertoire. Surprisingly, we find that shared antigen exposure to CMV leads to fewer shared TCR{beta} clones, even after controlling for HLA, indicative of a largely private response to major viral antigenic exposure. Consistent with this hypothesis, we find that increased age is correlated with decreased overall TCR{beta} clone sharing, indicating that the pattern of private TCR{beta} clonal expansion is a general feature of the T-cell response to other infectious antigens. All of these factors contribute to shaping the TCR{beta} repertoire, and understanding their interplay has important implications for the use of T cells for therapeutics and diagnostics.

immunology↗