SAP Protein-Dependent Natural Killer T-like Cells Regulate the Development of CD8+ T Cells with Innate Lymphocyte Characteristics

Abstract

SUMMARY CD8+ T cells are selected via low affinity interaction with MHC class I molecules on thymic epithelial cells (TECs). However, compromised T cell receptor signaling was proposed to force CD8+ T cell selection on hematopoietic cells through a SLAM-associated protein (SAP)-dependent mechanism similar to NKT cells. The outcome is an unconventional CD8+ T cell with phenotypic and functional characteristics of innate lymphocytes. Here we showed that Id3−/ − CD8+ T cells had an innate-like phenotype and required SAP for their development. However, like conventional CD8+ T cells, Id3−/ − CD8+ thymocytes were selected on TECs. The requirement for SAP and the innate-like phenotype was not intrinsic to Id3−/ − CD8+ thymocytes. Rather, an expanded population of NKT-like cells induced the innate phenotype on CD8+ T cells through production of interleukin-4. Our findings reveal that accumulation of NKT-like cells promotes conventional CD8+ thymocytes to acquire innate lymphocyte characteristics.

Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells

“…Specifically, thymocytes deficient in transcription factors such as Klf2, Itk, or Id3 aberrantly produce IL-4 that mediates the generation of such cells (30,(44)(45)(46). These studies collectively highlight the importance and complexity of transcription factor-dependent shaping of thymic cytokine levels to ensure normal development of various thymus-derived populations.…”

Positive selecting cell type determines the phenotype of MHC class Ib-restricted CD8 + T cells

“…Using M3/LemAspecific TCR Tg mice, we demonstrate that M3-restricted CD8 + T cells with identical TCRs can be selected on either TECs (D7 TEC s) or HCs (D7 HC s), giving rise to two phenotypically and functionally divergent populations. Interestingly, recent studies have suggested a model in which IL-4-producing PLZF + T cells are responsible for regulating the innate phenotype of MHC Iarestricted CD8 + T cells found in KLF2-and Id3-deficient animals (32,33). We were, however, unable to detect PLZFexpressing T cells in the thymus of D7 Tg mice, suggesting that differences in selecting cell type are sufficient to regulate the development of an innate-like phenotype in M3-restricted CD8 + T cells.…”

Development and Function of Innate Polyclonal TCRαβ+ CD8+ Thymocytes

“…However, it is less clear how deletion of Klf2, which causes expansion of innate CD8 T cells, could affect the strength of TCR signals during positive selection, inasmuch as Klf2 is not expressed in double-positive thymocytes (8). Furthermore, the hypothesis that innate CD8 T cells are selected by strong TCR signals is difficult to reconcile with reports that IL-4 produced by NKT cells can confer this innate phenotype on the majority of CD8 T cells (11,13). Therefore, a plausible hypothesis is that the key element is not the strength of the TCR signal per se but rather the perceived TCR signal strength (13).…”

“…+ TCRab T cells found in the thymus of mice deficient for ITK/RLK kinases or transcription factors (ID3, KLF2) (4,(11)(12)(13) or expressing an Lck-PLZF transgene (14). In these mutant mice, accumulation of polyclonal innate TCRab CD8 T cells is caused by expansion of PLZF + NKT cells that secrete large amounts of IL-4 (8).…”