The diversity of MAIT cells across the human body and in COVID-19

MAIT cells guard the immune homeostasis of barrier sites across the human body and circulate through peripheral blood, constantly patrolling for signals of infection and inflammation. Despite their presence in virtually every organ, our knowledge of the immunobiology of MAIT cells in the human immune system is largely limited to peripheral blood. The aim of this thesis is to advance our knowledge on the role of MAIT cells in human tissue immunology. To this end, we explored the distribution, activation, and functional adaptation of MAIT cells across different human tissues, particularly in response to viral disease such as COVID-19.

In Study I, we characterized human MAIT cells in donor-matched organs or blood and detected compartmentalization patterns regarding population size and site- specific adaptations. We demonstrate heterogeneity of MAIT cells within the same individual, featuring a CD39hi CD27low barrier-protective phenotype in the gut and a dynamically adoptable, liver-dominant CD56-associated enhanced effector program.

In Study II, we monitor the dynamics of MAIT cell activity in patients suffering from acute COVID-19. We detected a decline of MAIT cells in circulation and a recruitment to the inflamed lungs of COVID-19 patients. MAIT cells were highly inflammatory in the infected airways, and circulating MAIT cells showed signs of residual activation which was associated with disease severity.

In Study III, we followed the survivors of severe COVID-19 in longitudinal-paired analysis and detected a transient inconsistent recovery of MAIT cells. In the early resolution phase of the disease, MAIT cells normalized numerically in the circulation, but remained residually activated. In later convalescence, MAIT cell numbers declined, and were functionally impaired in a subset of patients exhibiting an exhausted PD-1high phenotype.

Together, this thesis explores the role of MAIT cells in human mucosal immunology to shed light on aspects of MAIT cell diversity in health and viral disease.

List of scientific papers

I. Kammann T, Cai C, Sekine T, Mouchtaridi E, Boulouis C, Nilsén V, Rivera-Ballesteros O, Müller TR, Gao Y, Raineri EJM, Akhirunnesa M, Adamo S, Constantz C, Niessl J, Weigel W, Kokkinou E, Stamper C, Marchalot A, Bassett J, Ferreira S, Rødahl I, Wild N, Brownlie D, Tibbitt C, Mak JYW, Fairlie DP, Leeansyah E, Michaelsson J, Marquardt N, Mjösberg J, Jorns C, Buggert M, Sandberg JK. MAIT cell heterogeneity across paired human tissues reveals specialization of distinct regulatory and enhanced effector profiles. Sci Immunol. 2024; 9(99):eadn2362. https://doi.org/10.1126/sciimmunol.adn2362

II. Parrot T*, Gorin JB*, Ponzetta A, Maleki KT, Kammann T, Emgård J, Perez-Potti A, Sekine T, Rivera-Ballesteros O, Karolinska COVID-19 Study Group, Gredmark-Russ S, Rooyackers O, Folkesson E, Eriksson LI, Norrby-Teglund A, Ljunggren HG, Björkström NK, Aleman S, Buggert M, Klingström J, Strålin K, Sandberg JK. MAIT cell activation and dynamics associated with COVID-19 disease severity. Sci Immunol. 2020; 5(51):eabe1670. https://doi.org/10.1126/sciimmunol.abe1670

III. Kammann T*, Gorin JB*, Parrot T*, Gao Y, Ponzetta A, Emgård J, Maleki KT, Sekine T, Rivera-Ballesteros O, Karolinska COVID-19 Study Group, Gredmark-Russ S, Rooyackers O, Skagerberg M, Eriksson LI, Norrby-Teglund A, Mak JYW, Fairlie DP, Björkström NK, Klingström J, Ljunggren HG, Aleman S, Buggert M, Strålin K, Sandberg JK. Dynamic MAIT Cell Recovery after Severe COVID-19 Is Transient with Signs of Heterogeneous Functional Anomalies. J Immunol. 2024; 212(3):389- 396. https://doi.org/10.4049/jimmunol.2300639

* contributed equally