Durable Expansion of TCR-δ Meta-Clonotypes After BCG Revaccination in Humans

Frontiers in Immunology

卷:13

Krystle K. Q. Yu¹  Malisa T. Smith¹  Charlotte A. James¹  Erik D. Layton¹  Thomas J. Scriba²  Willem A. Hanekom²  John L. Johnson³  Chetan Seshadri⁴  Andrew Fiore-Gartland⁵  Koshlan Mayer-Blackwell⁵ 

[1] Department of Medicine, University of Washington, Seattle, WA, United States;

[2] South African Tuberculosis Vaccine Initiative and Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa;

[3] Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, United States;

[4] Tuberculosis Research and Training Center, University of Washington, Seattle, WA, United States;

[5] Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States;

关键词: BCG - Bacille Calmette-Guérin vaccine;    tuberculosis;    gamma delta (γδ) T cells;    donor unrestricted T cells;    MAIT cell;    iNKT cell;   

DOI  :  10.3389/fimmu.2022.834757

来源: DOAJ

【 摘 要 】

Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used for 100 years and prevents disseminated tuberculosis and death in young children. However, it shows only partial efficacy against pulmonary tuberculosis (TB) in adults, so new vaccines are urgently needed. The protective efficacy of BCG depends on T cells, which are typically activated by pathogen-derived protein antigens that bind to highly polymorphic major histocompatibility complex (MHC) molecules. Some T cells recognize non-protein antigens via antigen presenting systems that are independent of genetic background, leading to their designation as donor-unrestricted T (DURT) cells. Whether live whole cell vaccines, like BCG, can induce durable expansions of DURT cells in humans is not known. We used combinatorial tetramer staining, multi-parameter flow cytometry, and immunosequencing to comprehensively characterize the effect of BCG on activation and expansion of DURT cell subsets. We examined peripheral blood mononuclear cells (PBMC) derived from a Phase I study of South African adults in which samples were archived at baseline, 3 weeks, and 52 weeks post-BCG revaccination. We did not observe a change in the frequency of total mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, germline encoded mycolyl-reactive (GEM) T cells, or γδ T cells at 52 weeks post-BCG. However, immunosequencing revealed a set of TCR-δ clonotypes that were expanded at 52 weeks post-BCG revaccination. These expanded clones expressed the Vδ2 gene segment and could be further defined on the basis of biochemical similarity into several ‘meta-clonotypes’ that likely recognize similar epitopes. Our data reveal that BCG vaccination leads to durable expansion of DURT cell clonotypes despite a limited effect on total circulating frequencies in the blood and have implications for defining the immunogenicity of candidate whole cell TB vaccines.

【 授权许可】

Unknown