The Transcription Factor T-bet Is Induced by IL-15 and Thymic Agonist Selection and Controls CD8αα+ Intraepithelial Lymphocyte Development

Abstract

CD8αα(+) intraepithelial lymphocytes (IELs) are instrumental in maintaining the epithelial barrier in the intestine. Similar to natural killer cells and other innate lymphoid cells, CD8αα(+) IELs constitutively express the T-box transcription factor T-bet. However, the precise role of T-bet for the differentiation or function of IELs is unknown. Here we show that mice genetically deficient for T-bet lacked both TCRαβ(+) and TCRγδ(+) CD8αα(+) IELs and thus are more susceptible to chemically induced colitis. Although T-bet was induced in thymic IEL precursors (IELPs) as a result of agonist selection and interleukin-15 (IL-15) receptor signaling, it was dispensable for the generation of IELPs. Subsequently, T-bet was required for the IL-15-dependent activation, differentiation, and expansion of IELPs in the periphery. Our study reveals a function of T-bet as a central transcriptional regulator linking agonist selection and IL-15 signaling with the emergence of CD8αα(+) IELs.

Diverse developmental pathways of intestinal intraepithelial lymphocytes

“…By contrast, IL-15-induced signalling was crucial for the maturation and/or survival of unconventional TCRαβ + IELs in the periphery. T-bet-deficient mice also lack intestinal IELs, which is consistent with an important role for the IL-15–T-bet–RUNX3 axis in their development 63,65 .…”

IL-1β and IL-23 Promote Extrathymic Commitment of CD27+CD122− γδ T Cells to γδT17 Cells

“…IL-15 shares CD122 and CD132 as receptor molecules with IL-2 and thus, like IL-2, also belongs to the family of common g-chain cytokines. While suppressing gdT17 cells, IL-15 has been shown to promote gdT1 development in the thymus by induction of T-bet in CD8aa precursors (42). Altogether, it is intriguing to speculate that common g-chain cytokines might be an important determinant in dictating the balance of gdT1 versus gdT17 cells during thymic development.…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…This phenomenon is supported by the notion that at least one T-box TF, in particular T-bet, is necessary to maintain the expression of cytokine receptor subunit CD122 (IL-2/IL-15R β chain), which delivers a survival signal to certain memory T cell populations. 60,140,141 However, the requirement of IL-15 in the long-term survival of T RM s is tissue type-dependent. 94 Whether IL-15-independent T RM s requires residual expression of CD122 and T-bet remains to be clarified.…”