The antimicrobial role of human MAIT cells

MAIT cells are unconventional T cells that have characteristics of both innate and adaptive immunity. Their fast mobilization and wide distribution in tissues make them part of the first line of defense against infection. MAIT cells recognize riboflavin-related metabolites produced by bacteria and presented by MR1. However, they can also sense viral infection through non-specific activation by cytokines. MAIT cells respond rapidly with secretion of cytokines and degranulation of cytolytic molecules, and play an important role in immune defense. This thesis work aimed to further explore the function of MAIT cells in different contexts.

First, we explored the interaction between humoral IgG responses and MAIT cells in antibacterial immunity. Here, MAIT cell responses to IgG-opsonized bacteria were compared to responses against non-opsonized bacteria. MAIT cell responses against opsonized Escherichia coli were stronger, with an increased magnitude and faster kinetics. Furthermore, MAIT cells were activated at lower bacterial doses when opsonized. We deciphered the mechanism responsible for the MAIT cell boost of function and showed that FcγR triggering by the opsonized bacteria was essential to increase MR1 antigen presentation. The boost of function was validated in a vaccine setting, where we used sera from individuals before and after vaccination against Streptococcus pneumoniae to opsonize one vaccine strain. MAIT cell functions were boosted when stimulated with S. pneumoniae opsonized with sera drawn after vaccination. In the second project, we investigated the cytolytic mechanisms used by MAIT cells against E. coli. Interestingly, MAIT cells not only killed E. coli-infected cells but also controlled cell-associated bacterial load through degranulation. More precisely, Granzyme B (GzmB), Granulysin (Gnly), and perforin were involved in the killing. MAIT cell activity was maintained against carbapenem-resistant E. coli (CREC). CREC strains use two main mechanisms of resistance: production of carbapenemases that inactivate carbapenem antibiotics, and membrane impermeability by porin-loss or over-expression of efflux pumps that block antibiotic penetration in the bacteria. Interestingly, MAIT cell- derived Gnly and GzmB were able to damage the membrane of free-living CREC. This effect was further enhanced by the addition of carbapenem antibiotic, suggesting a synergy between the cytotoxic proteins and the antibiotic. This also implied that MAIT cells may overcome the impermeability mechanism of resistance of CREC. In the third project, we investigated if some bacteria can adapt to escape from MAIT cell responses through immune evasion mechanisms. Staphylococcus aureus produces the pore-forming toxin leukotoxin ED (LukED) that binds to CCR5. We found that MAIT cells were hypersensitive to LukED and this was due to very high expression of CCR5 on MAIT cells. Within the T cell pool, MAIT cells were the most severely depleted population indicating that LukED secretion constitutes an immune evasion mechanism from MAIT cell recognition.

In conclusion, these findings indicate that MAIT cell responses are boosted against IgG- opsonized pathogens. Furthermore, MAIT cell cytolytic activity is maintained against CREC, and GzmB and Gnly synergize with carbapenem antibiotics to kill free-living CREC. Finally, some bacteria have developed means to evade MAIT cell responses, and this includes LukED secretion by S. aureus, which strongly targets MAIT cells. Overall, this thesis work enhances our understanding of MAIT cells as important antimicrobial immune cells.

List of scientific papers

I. Boulouis C, Gorin JB, Dias J, Bergman P, Leeansyah E, Sandberg JK. Opsonization-Enhanced Antigen Presentation by MR1 Activates Rapid Polyfunctional MAIT Cell Responses Acting as an Effector Arm of Humoral Antibacterial Immunity. J Immunol. 2020 Jul 1; 205(1):67-77.
https://doi.org/10.4049/jimmunol.2000003

II. Boulouis C*, Sia WR*, Gulam MY, T eo JQM, Png YT, Phan TK, Mak JYW, Fairlie DP, Poon IKH, Koh TH, Bergman P, Lim CM, Wang LF, Kwa ALHo, Sandberg JKo, Leeansyah E. Human MAIT cell cytolytic effector proteins synergize to overcome carbapenem resistance in Escherichia coli. PLoS Biol. 2020 Jun 8; 18(6), e3000644. *Contributed equally, oContributed equally.
https://doi.org/10.1371/journal.pbio.3000644

III. Boulouis C, Leeansyah E, Shambat S.M., Norrby-Teglund Ao, Sandberg JKo. High sensitivity to leukocidin ED indicates a Staphylococcus aureus immune evasion mechanism targeting MAIT cells. oContributed equally. [Manuscript]