Abstract
Conventional T cells exhibit a delayed response to the initial priming of peptide antigens presented by major histocompatibility complex (MHC) proteins. Unlike conventional T cells, mucosal-associated invariant T (MAIT) cells quickly respond to non-peptidic metabolite antigens presented by MHC-related protein 1 (MR1). To elucidate the MR1-dependent activation program of MAIT cells in response to mycobacterial infections, we determined the surface markers, transcriptomic profiles, and effector responses of activated human MAIT cells. Results revealed that mycobacterial-incubated antigen-presenting cells stimulated abundant human CD8+ MAIT cells to upregulate the co-expression of CD69 and CD26, as a combinatorial activation marker. Further transcriptomic analyses demonstrated that CD69+CD26++ CD8+MAIT cells highly expressed numerous genes for mediating anti-mycobacterial immune responses, including pro-inflammatory cytokines, cytolytic molecules, NK cell receptors, and transcription factors, in contrast to inactivated counterparts CD69+/−CD26+/− CD8+MAIT cells. Gene co-expression, enrichment, and pathway analyses yielded high statistical significance to strongly support that activated CD8+ MAIT cells shared gene expression and numerous pathways with NK and CD8+ T cells in activation, cytokine production, cytokine signaling, and effector functions. Flow cytometry detected that activated CD8+MAIT cells produced TNFα, IFNγ, and granulysin to inhibit mycobacterial growth and fight mycobacterial infection. Together, results strongly support that the combinatorial activation marker CD69+CD26++ labels the activated CD8+MAIT cells that develop an innate-like activation program in anti-mycobacterial immune responses. We speculate that the rapid production of anti-mycobacterial effector molecules facilitates MAIT cells to fight early mycobacterial infection in humans.
Highlights
Innate and adaptive immune systems have framed a classical dichotomy of immune responses in health and diseases
The bacterial-incubated monocyte-derived dendritic cells (MoDCs) were washed and cocultured with a human mucosal-associated invariant T (MAIT) cell line (D466F5), which was derived from MAIT cells of an active tuberculosis patient [7]
As measured in an Enzyme-linked Immunospot (ELISPOT) assay, the number of interferon γ (IFNγ)+MAIT cell spots significantly enhanced upon the overnight stimulation (15 h of co-culture) of Bacille CalmetteGuerin (BCG)- and E.coli-incubated MoDCs, to an extent much higher than the non-infected condition or the background response of MoDCs (Figures 1A,B)
Summary
Innate and adaptive immune systems have framed a classical dichotomy of immune responses in health and diseases. Labeling the mycobacterial-reactive MAIT cells and defining their activation program regarding its similarities to conventional T cell or innate cells will facilitate the understanding of their unique activation pathways and effector functions in antimycobacterial responses. The fundamental explanation of this “innate-like” MAIT cell activation initially bases on the evidence that MAIT cells express an invariant TCRα chain to interact with a conserved metabolite antigen presented by a monomorphic MR1 protein [12,13,14,15,16,17] This conservation interestingly contrasts to the trimolecular interaction for conventional T cell activation using heterogeneous TCRs to recognize variable peptide antigens presented by heterogeneous HLA molecules [1, 2]. Results revealed that CD69+CD26++ CD8+MAIT cells shared key gene expression and activation pathways with conventional CD8+ T cells and NK cells, supporting a unique “innate-like” activation program to induce early anti-mycobacterial responses
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call