Shared and Distinct Phenotypes and Functions of Human CD161++ Vα7.2+ T Cell Subsets

Abstract

Human mucosal-associated invariant T (MAIT) cells are an important T cell subset that are enriched in tissues and possess potent effector functions. Typically such cells are marked by their expression of Vα7.2-Jα33/Jα20/Jα12 T cell receptors, and functionally they are major histocompatibility complex class I-related protein 1 (MR1)-restricted, responding to bacterially derived riboflavin synthesis intermediates. MAIT cells are contained within the CD161++ Vα7.2+ T cell population, the majority of which express the CD8 receptor (CD8+), while a smaller fraction expresses neither CD8 or CD4 coreceptor (double negative; DN) and a further minority are CD4+. Whether these cells have distinct homing patterns, phenotype and functions have not been examined in detail. We used a combination of phenotypic staining and functional assays to address the similarities and differences between these CD161++ Vα7.2+ T cell subsets. We find that most features are shared between CD8+ and DN CD161++ Vα7.2+ T cells, with a small but detectable role evident for CD8 binding in tuning functional responsiveness. By contrast, the CD4+ CD161++ Vα7.2+ T cell population, although showing MR1-dependent responsiveness to bacterial stimuli, display reduced T helper 1 effector functions, including cytolytic machinery, while retaining the capacity to secrete interleukin-4 (IL-4) and IL-13. This was consistent with underlying changes in transcription factor (TF) expression. Although we found that only a proportion of CD4+ CD161++ Vα7.2+ T cells stained for the MR1-tetramer, explaining some of the heterogeneity of CD4+ CD161++ Vα7.2+ T cells, these differences in TF expression were shared with CD4+ CD161++ MR1-tetramer+ cells. These data reveal the functional diversity of human CD161++ Vα7.2+ T cells and indicate potentially distinct roles for the different subsets in vivo.

MAIT cells and viruses

“…It still holds true that this population as a whole hase conserved characteristics, which also extend into related CD161‐expressing innate T cell populations (see below) . It is also the case that such MAIT cell functionality appears to be more or less identical when comparing the CD8 + and the CD8 − CD4 − double negative population of MAIT cells (which also express high levels of CD161) …”

“…There may be a positive feedback loop as the percentage of MAIT cells expressing CD94 increased with IL‐12 and IL‐18 stimulation . Additionally, functional differences may also be observed in the relatively rare CD4 + MAIT cell subset …”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…Thus, both CD56 dim NK cells and CD161+ CD8+ T‐cells are enriched for Eomes+T‐bet high cells,16, 107 while CD56 bright NK cells have an Eomes+T‐bet low phenotype,107 which is mirrored by CD8+ MAIT cells 108. Of note, CD161+ CD8+ T‐cells express higher levels of GrB and perforin even compared with their CD161− CD8+ T‐cell counterparts, although both populations contain similar frequencies of effector memory T‐cells and terminally differentiated CD8+ T‐cells 16…”

MAIT cell-mediated cytotoxicity: Roles in host defense and therapeutic potentials in infectious diseases and cancer

“…For instance, CD94, which associates with NKG2A, −C, −E, and −F to recognize the MHC class Ib molecule HLA‐E, is not uniformly expressed by all PB MAIT cells . Of note, NKG2A is detectable in a small proportion of PB MAIT cells, but neither CD94 nor NKG2A is found on the CD4 + subset . Importantly, when compared with their CD94 − , CD56 − , and CD84 − counterparts, MAIT cells expressing these molecules more readily produce IFN‐γ in response to IL‐12 and IL‐18 .…”