Unconventional T cells: Underlying biology and implications for Mycobacterium tuberculosis immunity

Abstract

T cells recognize foreign antigens through the T cell receptor (TCR). Conventional CD4 and CD8αβ T cells recognize peptide antigens presented by major histocompatibility complex (MHC) molecules and have long been considered a crucial component of the immune response to infection by Mycobacterium tuberculosis (Mtb). However, vaccine strategies targeting conventional T cells have failed to provide protection against Mtb infection. Unconventional T cell subsets that recognize non-peptide antigens independently of MHC additionally participate in Mtb immunity. These include CD1b-specific T cells, mucosal-associated invariant T (MAIT) cells, γδ T cells, and CD8αα T cells. Unconventional T cells exhibit more innate-like functions, including rapid effector functions, enrichment at barrier tissues, and non-specific activation in response to pro-inflammatory cues (‘bystander activation’). Thus, unconventional T cells may be an alternative, novel target for vaccine strategies. In the following work, we characterized the mechanisms of activation and functional responses of CD1b-specific T cells and CD8αα T cells during mycobacterial immunity across multiple tissue types and species. Our studies on CD1b-restricted T cells focused on interrogating bystander activation responses and profiling immune responses to protective intravenous BCG (IV BCG) vaccination in non-human primates. We show that CD1b-specific T cells appear less responsive to bystander cues than MAIT cells but more responsive than conventional CD4 or CD8 T cells in the peripheral blood of humans and non-human primates. This activation is partially mediated by the IL-18 receptor (IL-18R). In response to IV BCG, CD1b-specific T cells expand in the lung, undergo terminal differentiation in the lung, and increase IL-18R expression in the periphery. The kinetics of CD1b GMM T cell expansion mirrored the kinetics of conventional T cells, while the differentiation into effector memory cells mirrored that observed in MAIT cells. These findings reveal both innate-like and adaptive responses of CD1b GMM-specific T cells to IV BCG vaccination, highlighting a potential contribution of bystander activation. CD8αα is a homodimeric coreceptor that is a counterpart to the CD8αβ heterodimeric coreceptor expressed on conventional CD8 T cells. While CD8αα is enriched among MAIT and γδ T cells, the coreceptor can also be expressed by T cells that do not fall within established unconventional T cell subsets. We profiled CD8αα T cells across human peripheral blood and mucosal tissue, determining that non-MAIT, non-γδ CD8αα T cells (CD8αα ‘other’ T cells) were the dominant CD8αα expressing cell type in both compartments. Despite attenuated activation in vitro, CD8αα ‘other’ T cells exhibited cytotoxic, activated, and pro-inflammatory responses to IV BCG. These responses showed evidence of TCR-mediated, rather than bystander-mediated, activation. Collectively, this body of work enhances our understanding of the mechanisms governing T cell activation and associated functional responses. Further, these data provide new insights into unconventional T cell responses elicited by a protective vaccination strategy, revealing the breadth of functional programs that may be required for protection against Mtb infection and disease.