Sensing mycobacteria through unconventional pathways

Abstract

Approximately one-quarter of the global population is estimated to be infected with Mycobacterium tuberculosis. New developments in vaccine design and therapeutics are urgently needed, particularly in the face of multidrug-resistant tuberculosis (TB). In this issue of the JCI, Sakai and colleagues used a multidisciplinary approach to determine that trehalose-6-monomycolate (TMM), a mycobacterial cell wall lipid, serves as a T cell antigen presented by CD1b. CD1b-TMM-specific T cells were characterized by conserved T cell receptor features and were present at elevated frequencies in individuals with active TB disease. These findings highlight the dual role of TMM in stimulating both innate and adaptive immunity and broaden our understanding of CD1-mediated lipid recognition by unconventional T cells.

Figure 1. Mycobacterial lipids play a dual role in stimulating the immune system.

The mycobacterial cell wall contains numerous MAs with immunostimulatory activity. Mycolate lipids such as TMM, TDM, and diacyltrehalose (DAT) bind to the C-type lectin receptor Mincle on myeloid cells, stimulating downstream inflammatory processes. Others such as LAM and PIM bind TLR2, which triggers GM-CSF secretion and CD1 upregulation on antigen-presenting cells, including myeloid cells, monocytes, and macrophages. These and other lipid-based molecules, such as MA or its ester derivatives GMM, DAT, and SGL, can also be captured by CD1b and presented to unconventional T cells that recognize such CD1b-lipid complexes via their TCR. The CD1b-TMM–specific T cell populations revealed by Sakai and colleagues (3) expand upon M. tuberculosis infection and exhibited conserved features shared across different individuals. Some of these characteristics are also common among other CD1b-restricted T cell subsets, including expression of the CD4 coreceptor and cytotoxicity-associated effector molecules, such as IFN, TNF, granzyme B (GzmB), and perforin. They also share a previously described TRBV4-1 usage for CD1b-restricted cells (albeit with long and flexible CDR3β loops to accommodate a complex lipid headgroup that protrudes from CD1b) and positively charged amino acids comprising the CDR3α (similar to CD1b-GMM–reactive cells), which define the TCR specificity for CD1b-TMM.