T-bet orchestrates CD8αα IEL differentiation

Abstract

Very little is known about the transcription factor network that regulates the development of intestinal intraepithelial lymphocytes (IELs). In this issue of Immunity, Klose et al. (2014b) and Reis et al. (2014) demonstrate an essential role for T-bet in regulating the CD8αα IEL differentiation program.

Figure 1.. T-bet Regulates the Differentiation of Natural and Induced CD8αα⁺ Intestinal Intraepithelial Lymphocytes

IEL populations comprise natural TCRαβ⁺CD8αα⁺ or TCRγδ⁺CD8αα⁺ cells derived from thymic precursors and induced TCRαβ⁺CD8αβ⁺CD8αα⁺ or TCRαβ⁺CD4⁺CD8αα⁺ cells derived from conventional peripheral T cells. (Bottom left) Thymic IEL precursors (IELp) express a low amount of IL-15R via a T-bet-dependent mechanism. Following the migration of IELp to the gut, intestinal epithelium-derived IL-15 triggers increased T-bet (encoded by Tbx21) expression, which in turn upregulates expression of CD122 (IL-15Rβ subunit), creating a positive feedback loop to promote CD8αα⁺ IEL maturation, survival, and proliferation. (Bottom right) Peripheral TCRαβ⁺ T cells upregulate T-bet expression upon exposure to TGF-β, retinoic acid (RA), and either IFN-γ or IL-27 in the intestinal milieu. T-bet activates the transcription factor Runx3, which induces the expression of CD103, CD8αα⁺, and other aspects of the CD8αα⁺ IEL differentiation program. T-bet also suppresses the T-helper lineage-specific factor Thpok and other conventional T-helper effector functions, thus promoting the conversion of conventional CD4⁺ T cells into induced CD8αα⁺ IELs.