Human Tissue-Resident Mucosal-Associated Invariant T (MAIT) Cells in Renal Fibrosis and CKD

Abstract

BackgroundMucosal-associated invariant T (MAIT) cells represent a specialized lymphocyte population associated with chronic inflammatory disorders. Little is known, however, about MAIT cells in diseases of the kidney, including CKD.MethodsTo evaluate MAIT cells in human native kidneys with tubulointerstitial fibrosis, the hallmark of CKD, we used multicolor flow cytometry to identify, enumerate, and phenotype such cells from human kidney tissue biopsy samples, and immunofluorescence microscopy to localize these cells. We cocultured MAIT cells and human primary proximal tubular epithelial cells (PTECs) under hypoxic (1% oxygen) conditions to enable examination of mechanistic tubulointerstitial interactions.ResultsWe identified MAIT cells (CD3+ TCR Vα7.2+ CD161hi) in healthy and diseased kidney tissues, detecting expression of tissue-resident markers (CD103/CD69) on MAIT cells in both states. Tissue samples from kidneys with tubulointerstitial fibrosis had significantly elevated numbers of MAIT cells compared with either nonfibrotic samples from diseased kidneys or tissue samples from healthy kidneys. Furthermore, CD69 expression levels, also an established marker of lymphocyte activation, were significantly increased on MAIT cells from fibrotic tissue samples. Immunofluorescent analyses of fibrotic kidney tissue identified MAIT cells accumulating adjacent to PTECs. Notably, MAIT cells activated in the presence of human PTECs under hypoxic conditions (modeling the fibrotic microenvironment) displayed significantly upregulated expression of CD69 and cytotoxic molecules perforin and granzyme B; we also observed a corresponding significant increase in PTEC necrosis in these cocultures.ConclusionsOur findings indicate that human tissue-resident MAIT cells in the kidney may contribute to the fibrotic process of CKD via complex interactions with PTECs.

Role of inflammation and inflammasome activation in human bile cast nephropathy

“…The subsequent production of IL‐1β and IL‐18 would activate tubulointerstitial T cells. Supporting this concept, we have previously reported high expression of interleukin receptors (eg, IL‐18R) on T lymphocytes in human kidney disease …”

Tissue‐resident mucosal‐associated invariant T (MAIT) cells in the human kidney represent a functionally distinct subset

“…Mucosal‐associated invariant T (MAIT) cells are innate‐like T‐cells involved in the antibacterial and antifungal response by recognizing riboflavin metabolites. They comprise 0.1‐10% of the T‐cell population in the peripheral blood and are abundant at barrier sites such as the liver, lungs, intestine, stomach, and the female genital mucosa [1–6]. MAIT cells are characterized by the expression of the semi‐invariant Vα7.2‐Jα12/20/33 chain of the TCR, which restricts them to the nonpolymorphic, MHC class I‐related protein MR1 [7–10].…”

“…Recently, MAIT cells were also shown to reside in the human kidney. These cells were found to express CD69 (a C‐type lectin) and CD103 (the integrin αE chain), marking them as tissue‐resident T cells [5].…”

Circulating mucosal‐associated invariant T cells in subjects with recurrent urinary tract infections are functionally impaired

“…8 Mucosalassociated invariant T (MAIT) cells are innate-like T cells that play a role in the antibacterial and antifungal response by recognizing riboflavin metabolites produced by these organisms. 9 MAIT cells comprise 0.1% to 10% of the circulating T-cell population, 10 are abundant in the liver, lungs, intestine, stomach, kidney, and the female genital mucosa [11][12][13][14][15] and can respond rapidly, that is, within hours, to a wide range of bacteria. 16,17 MAIT cells are characterized by the expression of the semi-invariant Vα7.2-Jα12/20/33 chain as a part of their T-cell receptor (TCR).…”