SARS-CoV2 mRNA-vaccination-induced Immunological Memory in Human Non-Lymphoid and Lymphoid Tissues

Abstract

Tissue-resident lymphocytes provide organ-adapted protection against invading pathogens. Whereas their biology has been examined in great detail in various infection models, their generation and functionality in response to vaccination has not been comprehensively analyzed in humans. We therefore studied SARS-CoV2 mRNA-vaccine-specific T cells in surgery specimens of kidney, liver, lung, bone marrow and spleen in comparison to paired blood samples from largely virus-naive individuals. As opposed to lymphoid tissues, non-lymphoid organs harbored significantly elevated frequencies of Spike-specific CD4+ T cells compared to paired peripheral blood showing hallmarks of tissue residency and an expanded memory pool. Organ-derived, vaccine-specific T helper (Th) cells were characterized by increased portions of multifunctional cells over those detected in blood. Single-cell RNA sequencing revealed functional rather than organ-specific clusters of Spike-reactive Th cells, indicating similar diversification programs across tissues. T cell receptor (TCR) repertoire analysis indicated that the TCR sequence is a major determinant of transcriptomic state in tissue-resident, vaccine-specific CD4+ T cells. In summary, our data demonstrate that SARS-CoV2 vaccination entails acquisition of tissue memory and residency features in organs distant from the inoculation site, thereby contributing to our understanding of how local tissue protection might be accomplished.