Publications

Multi-variate model of T cell clonotype competition and homeostasis

Published in Submitted to: Scientific Reports, 2022

The diversity of the naive T cell receptor repertoire is maintained by competition for homeostatic proliferation stimuli. We make use of a pre- viously defined bi-variate competition model to propose a multi-variate model to study the dynamics of $\eta$ different competing T cell clonotypes for stimuli provided by self-peptides bound to major histocompatibility complexes (self-pMHCs). We characterise the late time behaviour of the system by analysing: (i) its dynamics before extinction of the first clonotype, making use of the quasi-stationary probability distribution, (ii) the time to the first extinction event, (iii) the probability of extinction for each clonotype, and (iv) the size of the surviving clonotypes when the first extinction event takes place. Additionally we define and study the probability distribution of the number of divisions undergone by a clonotype before its extinction. Our results indicate that the mean size of a new clonotype at quasi-steady state increases as the total self-pMHC stimulus available to it increases, or as the fraction of self-pMHC stimuli shared with other clonotypes decreases. Furthermore, the competition experi- enced by a a new clonotype entering the homeostatic distribution of naive T cell clonotypes and its initial size are the most significant parameters since they determine its probability of extinction in the periphery.

Recommended citation: Daniel Luque Duque, Martín López García, Jessica A. Gaevert, Grant Lythe, Paul G. Thomas, and Carmen Molina-París. Multi-variate model of T cell clonotype competition and homeostasis. Submitted to: Scientific Reports, 2022

Pre-existing humoral immunity to human common cold coronaviruses negatively impacts the protective SARS-CoV-2 antibody response

Published in Cell Host & Microbe, 2022

SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoVs) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates that baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes the generation of SARS-CoV-2-neutralizing antibodies in mice. Together, these data suggest that pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants.

Recommended citation: Chun-Yang Lin, Joshua Wolf, David C Brice, Yilun Sun, Macauley Locke, Sean Cherry, Ashley H Castellaw, Marie Wehenkel, Jeremy Chase Crawford, Veronika I Zarnitsyna, Daniel Duque, Kim J. Allison, et al. Pre-existing humoral immunity to human common cold coronaviruses negatively impacts the protective SARS-CoV-2 antibody response. Cell Host & Microbe, volume 30, pages 83–96.e4. Elsevier, 2022. https://www.sciencedirect.com/science/article/pii/S1931312821005709

Quantifying T Cell Cross-Reactivity: Influenza and Coronaviruses

Published in Viruses, 2021

If viral strains are sufficiently similar in their immunodominant epitopes, then populations of cross-reactive T cells may be boosted by exposure to one strain and provide protection against infection by another at a later date. This type of pre-existing immunity may be important in the adaptive immune response to influenza and to coronaviruses. Patterns of recognition of epitopes by T cell clonotypes (a set of cells sharing the same T cell receptor) are represented as edges on a bipartite network. We describe different methods of constructing bipartite networks that exhibit cross-reactivity, and the dynamics of the T cell repertoire in conditions of homeostasis, infection and re-infection. Cross-reactivity may arise simply by chance, or because immunodominant epitopes of different strains are structurally similar. We introduce a circular space of epitopes, so that T cell cross-reactivity is a quantitative measure of the overlap between clonotypes that recognize similar (that is, close in epitope space) epitopes.

Recommended citation: Gaevert, J. A., Luque Duque, D., Lythe, G., Molina-París, C., & Thomas, P. G. (2021). Quantifying T Cell Cross-Reactivity: Influenza and Coronaviruses. Viruses, 13(9), 1786. https://www.mdpi.com/1999-4915/13/9/1786