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

Abstract

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.

Deep characterization of human γδ T cell subsets defines shared and lineage-specific traits

“…gd T cells have been broadly described as innate-like, but recent studies have revealed phenotypic and functional heterogeneity both between and within Vd1 and Vd2 responses including subpopulations displaying characteristics aligned with adaptive immunity (15)(16)(17)(18)(19). Either Vd1 or Vd2 T cells transiently expand in response to infection or malignancy.…”

Impact of BCG vaccination on the repertoire of human γδ T cell receptors

“…The absence of clonotypic expansions after infant BCG vaccination could be due to a lack of depth of analysis necessary to identify the relevant clonotypes, lack of full maturation of gd T cells in infants with poor expansion capacity after BCG vaccination, and/or the relative insufficiency of the g 9 d 2 T cell subset present in infancy compared with other subsets of gd T cells. Seshadri (19) et al used 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. They found TRDV*02+CACDTLLGDTRTDKLIF to be a metaclonotype associated with BCG vaccination, enriched post-BCG in 9 of 17 samples and persisting for 1 year.…”

Exploring HIV Vaccine Progress in the Pre-Clinical and Clinical Setting: From History to Future Prospects

“…In turn, BCG-trained monocytes boost responses to different exposures through non-antigen-specific mechanisms, including increased cytokine and chemokine release and the support of memory adaptive responses [ 253 ]. Recent findings also suggest that BCG induces sustained changes in the T cell repertoire, potentially contributing to long-term protection [ 254 ]. Applying trained immunity to enhance specific HIV responses across multiple clades is an intriguing concept, with trained monocytes initiating the response; this is followed by effective adaptive cytotoxic responses against conserved HIV regions.…”