At present, the factors driving the CD4+ bias of CD1b-TMM–restricted cells remain unclear. Interestingly, CD1b-GMM– and CD1b-SGL–specific cells are also biased toward CD4 usage (14, 16). While there is no evidence that coreceptors are required for CD1b recognition, both CD4 and CD8 can modulate the functional avidity of CD1b-reactive T cells by enhancing their CD3 and TCR expression and avidity (16). Thus, CD4 expression could reflect a thymus-acquired feature during T cell selection for higher-affinity TCRs and/or be associated with a particular functional program. Interestingly, Sakai and co-authors proposed that the CD4+ bias may reflect a role for MHC class II in selecting CD1b-TMM–reactive TCRs (3). Whereas unconventional T cells are presumed to be selected by their cognate MHC-I–like target, a conserved subset of skin-derived, CD1a-restricted T cells has been reported to cross-react with superantigens presented by HLA-DR (19). While CD1b-TMM–reactive cells did not express PLZF (3), the key unconventional T lineage–defining transcription factor (20), PLZF+ CD1b-reactive T cells have been reported in CD1-humanized mice (21). It therefore remains to be understood whether the CD4+ and PLZF– phenotypes of CD1b-TMM–reactive T cells represent a specific lineage or functional selection pathway.

In addition to clarifying the biogenesis of CD1b-TMM–reactive T cells, we can now begin to assess their antimycobacterial potential in vivo. A precise understanding of the responses that underpin protective immunity to TB disease and development of an efficacious vaccine for adults remain elusive. Despite the myriad ways in which unconventional T cells can mediate immune responses upon M. tuberculosis infection, a lack of knowledge of the precise antigens and responding leukocyte populations, as well as the limited availability of preclinical models have directly hampered our ability to understand their contributions to immunity against M. tuberculosis (17). This is particularly relevant for group 1 CD1–restricted T cells, as most rodent species lack orthologs of CD1a, CD1b, or CD1c. Consequently, nonhuman primates (NHPs) are key models for CD1 immunology. Validation of whether CD1b-TMM–restricted T cells exist in macaques will be important for the field, particularly since GMM, which is presented by CD1b in humans, is instead presented by CD1c in rhesus macaques (22). It remains unknown if the presentation of TMM or its analogs in humans and NHPs is permitted by other CD1 proteins.

A recent study showed that intravenous BCG administration is highly protective against active TB disease in NHPs (23), representing a unique opportunity to investigate correlates of protection. As the development of TNF and IFN-γ–producing CD4+ T cells in the airway is predictive of protection (24), it will be important to dissect the antigen specificity of these populations and determine whether they include CD1-restricted T cells. Furthermore, inclusion of various mycobacterium-derived CD1 antigens in CD1 tetramers as well as rationally designed vaccine candidates (25) and the study of humanized CD1-transgenic mice will provide new opportunities to track CD1-restricted T cell responses following immunization or mycobacterial infection (26). In particular, the ability of TMM to act as a T cell antigen and an adjuvant makes it an intriguing candidate for inclusion in novel vaccines.

Collectively, Sakai et al. (3) illustrate a successful multidisciplinary effort combining chemistry, structural and cellular immunology, bioinformatics, and mass spectrometry–based ligand discovery approaches to advance our understanding of CD1-mediated immunity. It reveals a CD1 antigen, offers insights into the molecular basis through which T cells recognize CD1b-presented targets, and highlights the multifaceted role that microbial lipids can play in stimulating both broad innate and highly specific adaptive immunity. Such advances are key to bolstering the development of new interventions to prevent and treat mycobacterial diseases.