Abstract
BackgroundAntimicrobial T cells play key roles in the disease progression of cancers arising in mucosal epithelial tissues, such as the colon. However, little is known about microbe-reactive T cells within human breast ducts and whether these impact breast carcinogenesis.MethodsEpithelial ducts were isolated from primary human breast tissue samples, and the associated T lymphocytes were characterized using flow cytometric analysis. Functional assays were performed to determine T-cell cytokine secretion in response to bacterially treated human breast carcinoma cells.ResultsWe show that human breast epithelial ducts contain mucosal associated invariant T (MAIT) cells, an innate T-cell population that recognizes specific bacterial metabolites presented by nonclassical MR1 antigen-presenting molecules. The MAIT cell population from breast ducts resembled that of peripheral blood in its innate lymphocyte phenotype (i.e., CD161, PLZF, and interleukin [IL]-18 receptor coexpression), but the breast duct MAIT cell population had a distinct T-cell receptor Vβ use profile and was markedly enriched for IL-17-producing cells compared with blood MAIT cells. Breast carcinoma cells that had been exposed to Escherichia coli activated MAIT cells in an MR1-dependent manner. However, whereas phorbol 12-myristate 13-acetate/ionomycin stimulation induced the production of both interferon-γ and IL-17 by breast duct MAIT cells, bacterially exposed breast carcinoma cells elicited a strongly IL-17-biased response. Breast carcinoma cells also showed upregulated expression of natural killer group 2 member D (NKG2D) ligands compared with primary breast epithelial cells, and the NKG2D receptor contributed to MAIT cell activation by the carcinoma cells.ConclusionsThese results demonstrate that MAIT cells from human breast ducts mediate a selective T-helper 17 cell response to human breast carcinoma cells that were exposed to E. coli. Thus, cues from the breast microbiome and the expression of stress-associated ligands by neoplastic breast duct epithelial cells may shape MAIT cell responses during breast carcinogenesis.
Highlights
Antimicrobial T cells play key roles in the disease progression of cancers arising in mucosal epithelial tissues, such as the colon
These results establish that a population of Vα7.2+ T cells is present in human breast ducts that can be classified as mucosal associated invariant T (MAIT) cells, in that they bind MR1 molecules loaded with the 5RU antigen and coexpress CD161, IL-18Rα, and PLZF
Because neoplastic cells often upregulate ligands for natural killer group 2 member D (NKG2D), and because the addition of an NKG2D blocking antibody resulted in a partial reduction of MAIT cell effector responses, it is possible that the NKG2D pathway promotes the ability of MAIT cells to detect and respond to breast carcinomas. Together, these findings underscore the likelihood that there exists a tripartite interaction among MAIT cells, breast duct epithelial cells, and the breast microbiome that may play a role in breast carcinogenesis or during the progression of established tumors
Summary
Antimicrobial T cells play key roles in the disease progression of cancers arising in mucosal epithelial tissues, such as the colon. Because T cells that are specific for microbial antigens are known to play key roles in the progression of tumors arising in epithelial layers of the intestine [9], the observation that the breast ducts contain microbial colonists raises the question whether antimicrobial T cells may contribute, either positively or negatively, to the genesis of breast cancers. Consistent with this possibility, the presence of cancerous tissue has been found to be associated with alterations to the microbiome of the local breast tissue [8]. A central obstacle to assessing the role of microbe-specific T cells in breast cancer is that little is known about the T-cell compartment found within human breast ducts, and the presence of T cells that recognize microbial antigens has not yet been established
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