Biology subjects

Greissl, J.

Publications and source records attributed to Greissl, J..

4 recordsLinked to original sources

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

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↗