Biology subjects

Zahid, H. J.

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

8 recordsLinked to original sources

bioRxiv2026

The Separable Organization of Immune Transcriptional Responses

Immune function depends on coordinated responses across diverse cell types, yet the organizing principles underlying this coordination remain uncertain. Here we analyze single-cell data of peripheral blood mononuclear cells from 12 donors exposed in vitro to 90 cytokines and find that, for a given donor and perturbation, transcriptional responses in one cell type can be transformed into corresponding responses in another through mappings that depend only on the identities of the two cell types. These cross-cell-type mappings admit a separable organization in which each donor-perturbation pair is represented by a response state shared across cell types, while donor- and perturbation-independent cell-type-specific response rules specify how that state is expressed. We formalize this organization as a linear shared-state model that captures most of the reproducible transcriptional response variance. This separation between shared response state and cell-type-specific response rules generalizes to unseen donors and perturbations and extends to longitudinal variation in vivo. Thus, our results reveal an organizing principle of immune coordination, with distinct transcriptional responses across cell types representing cell-type-specific expressions of a shared donor-level response state.

immunology↗

bioRxiv2026

Immune System Organization is Encoded in Transcription

Immune responses are often interpreted as cell type-specific transcriptional programs driven by external stimuli, with variation typically analyzed within each cell type. Here we show that immune organization is reflected in coordinated changes in gene expression across cell types within individuals, forming a shared low-dimensional state space. Using single-cell transcriptomes from a large longitudinal cohort, we find that thousands of genes vary coherently relative to subtype-specific reference profiles, defining this low-dimensional structure. Across individuals and over time, these deviations organize into a small number of recurring, temporally stratified patterns of transcriptional change. Dominant patterns reflect temporal dynamics shared across individuals, whereas others encode stable individual-specific transcriptional configurations. This donor-level coordination is observed across tissues, is reflected in cell surface protein expression and is captured in matched serum proteomics. Importantly, responses to in vitro cytokine stimulation are coordinated across cell types within donors, demonstrating that donor-level transcriptional organization is preserved under perturbation. Together, these results show that donor-level organization is evident in both transcriptional state and responses to perturbation, manifesting across cell types, tissues and time.

immunology↗

bioRxiv2026

HLA Alleles Imprint Distinct Biases in the Usage Preferences of TCR Vβ segments

T cells must co-recognize peptide and HLA, yet the extent to which this specificity is shaped by germline-encoded TCR-HLA contacts versus selection during thymic development has remained difficult to quantify. Leveraging population-scale TCR{beta} repertoires linked to donor HLA genotypes, we construct allele-specific V{beta} usage profiles and normalize them to repertoire-wide baselines to derive interpretable HLA-TCR V{beta} preference vectors. We demonstrate that different HLA alleles imprint distinct biases in the usage frequency of TCR V{beta} gene segments among the public TCRs that engage those alleles; consistent with germline-encoded TCR-HLA contact preferences, certain V{beta} genes are over-represented for particular HLA alleles. Similarities in HLA amino-acid sequence predict similarities in both their V{beta} preferences and peptide-binding motifs; a residue-level analysis disentangles HLA positions primarily associated with TCR engagement from those associated with peptide motifs. The TCR-associated HLA positions localize to canonical TCR-facing helices, whereas peptide-associated HLA positions track binding pockets, revealing distinct molecular routes by which HLA polymorphism shapes the TCR and peptide sides of recognition. CMV exposure stratifications confirmed these patterns are not explained by a few dominant infections. Together, these data support that germline-encoded constraints set the landscape of TCR-HLA compatibility, while thymic and peptide-driven forces tune the realized repertoire. These HLA-specific V{beta} biases are a biological prior that should provide a baseline for better understanding of TCR-pHLA specificity as a whole and should be accounted for in future evaluation of any TCR-pHLA specificity prediction methods.

immunology↗

bioRxiv2025

A Fundamental Relationship between TCR Diversity, Repertoire Size and Systemic Clonal Expansion: Insights from 30,000 TCRβ Repertoires

TCR diversity is essential for immune defense, yet the mechanisms underlying its decline with age, its dependence on sex and its variation among individuals remain poorly understood. These patterns are often attributed to passive loss from factors such as thymic atrophy and cumulative immune exposures but such processes fail to explain the systematic variation observed across populations. Here we challenge this view by analyzing TCR{beta} repertoires from[~] 30, 000 individuals showing that TCR diversity is almost entirely determined by repertoire size and the frequency of the 1,000 most abundant clones. These two intrinsic features of the repertoire explain 96% of the variance in TCR diversity, capturing its dependence on age and sex and defining a robust relationship that holds even under strong immune perturbations such as Cytomegalovirus infection. This relationship arises because the frequency of abundant clones captures a repertoire-wide pattern of coordinated clonal expansion--termed intrinsic clonality--which may be a fundamental, previously unrecognized property of the immune system. We propose that TCR diversity emerges as a system-level property mediated by repertoire size and intrinsic clonality, both of which are likely homeostatically regulated. These findings offer a new conceptual framework for understanding TCR diversity within immune homeostasis which may guide therapies aimed at restoring immune function.

immunology↗

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↗