Biology subjects

Zahid, H. J.

Publications and source records attributed to Zahid, H. J..

4 recordsLinked to original sources

bioRxiv2024

T Cell Receptor Diversity, Cancer and Sex: Insights from 30,000 TCRβ Repertoires

Immunoediting posits that mutation and immunity jointly shape cancer evolution, yet their population-level interplay remains uncertain. Here we analyze T cell receptor (TCR) {beta} repertoires from 30,000 individuals and find that TCR diversity, essential for recognizing and eliminating malignant cells, declines with age. This immune decline occurs 11 years later in females and coincides with their lower cancer incidence, suggesting a biological connection. To test this link, we formalize immunoediting as a quantitative model of carcinogenesis, relating the measured age-associated decline in TCR diversity to rising cancer incidence. We find that both mutational and immune processes shape cancer risk, with lower incidence in females attributable to delayed immune decline. Extending this analysis across subtypes uncovers structured patterns in cancer incidence that reflect the relative contributions of these processes. Cancers cluster along an emergent immune-mutation axis that aligns with known features of cancer biology and indicates convergent evolutionary dynamics. Together, our results establish a quantitative, population-level framework for immunoediting that connects direct measurements of immune competence to cancer risk, integrating the molecular mechanisms, evolutionary dynamics and incidence patterns of cancer to reveal a fundamental balance between mutation and immunity that underlies carcinogenesis.

cancer biology↗

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↗

bioRxiv2024

Large-scale statistical mapping of T-cell receptor β sequences to Human Leukocyte Antigens

T-cell receptors (TCRs) interacting with peptides presented by human leukocyte antigens (HLAs) are the foundation of the adaptive immune system but population-level analysis of TCR-HLA interactions is lacking. Here we statistically associate[~] 106 public TCRs to specific HLAs using the TCR{beta} repertoires sampled from 4,144 HLA-genotyped subjects. The TCRs we associate are specific to unique HLA allotypes, not allelic groups, and to the paired -{beta} heterodimer of class II HLAs though exceptions are observed. This specificity permits highly accurate imputation of 248 class I and II HLAs from the TCR{beta} repertoire. Notably, 45 HLA-DP and -DQ heterodimers lack associated TCRs because they likely arise from non-functional trans-complementation. The public class I and II HLA-associated TCRs we identify are primarily expressed on CD8+ and CD4+ memory T cells, respectively, which are responding to various common antigens. Our results recapitulate fundamental biology, provide insights into the functionality of HLAs and demonstrate the power and potential of population-level TCR repertoire sequencing.

immunology↗

bioRxiv2024

Identifying immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors

BackgroundMemory T cells are records of clonal expansion from prior immune exposures such as infections, vaccines and chronic diseases. Some of the receptors of these expanded T cell clones in a typical immune repertoire are highly public (present in many individuals) because they respond to the same peptide from a prevalent immune exposure, presented by the same Human Leukocyte Antigen (HLA) allele. Only a tiny fraction of public T-cell receptor {beta} sequences (TCRs) have known associations with exposures or specific peptides. MethodsWe mined the TCR repertoires of tens of thousands of donors to define "ECOclusters": clusters of public TCRs that tend to occur in the same donors. First, we built models to infer donor HLA type from the TCR repertoire, then associated public TCRs with HLA alleles. Next, we derived co-occurrence clusters of TCRs responding to antigens presented by the same HLA allele, then combined those clusters by co-occurrence across HLA alleles. Each such cross-HLA ECOcluster putatively represents a public TCR signature of a single exposure. ResultsWe constructed sensitive, specific models to predict the presence of 220 HLA alleles from TCR repertoires and clustered 8,618,285 HLA allele-associated TCRs to define 11,058 ECOclusters. Using serologically labeled repertoires, we identified ECOclusters associated with HSV-1, HSV-2, EBV, Parvovirus, Toxoplasma gondii, Cytomegalovirus and SARS-CoV-2, and constructed sensitive, specific classifiers of exposure. ECOclusters represent a step toward deciphering the ledger of immune exposure history encoded by the T-cell repertoire.

immunology↗