Homeostasis of Vα14i NKT cells

105

125

The Tec kinases Itk and Rlk are required for efficient positive selection of conventional CD4+ and CD8+ T cells in the thymus. In contrast, recent studies have shown that these Tec kinases are dispensable for the development of CD8+ T cells with characteristics of innate T cells. These findings raise questions about the potential role of Itk and Rlk in NKT cell development, because NKT cells represent a subset of innate T cells. To address this issue, we examined invariant NKT cells in Itk−/− and Itk/Rlk−/− mice. We find, as has been reported previously, that Itk−/− mice have reduced numbers of NKT cells with a predominantly immature phenotype. We further show that this defect is greatly exacerbated in the absence of both Itk and Rlk, leading to a 7-fold reduction in invariant NKT cell numbers in the thymus of Itk/Rlk−/− mice and a more severe block in NKT cell maturation. Splenic Itk−/− and Itk/Rlk−/− NKT cells are also functionally defective, because they produce little to no cytokine following in vivo activation. Tec kinase-deficient NKT cells also show enhanced cell death in the spleen. These defects correlate with greatly diminished expression of CD122, the IL-2R/IL-15R β-chain, and impaired expression of the T-box transcription factor, T-bet. These data indicate that the Tec kinases Itk and Rlk provide important signals for terminal maturation, efficient cytokine production, and peripheral survival of NKT cells.

Section: Tec Family Kinase-deficient Nkt Cells Show Impaired Survivalsupporting

confidence: 87%

mentioning

confidence: 99%

The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival

Felices

Berg

2008

105

125

“…Similar to the case with TCR␥␦ s-IEL, enforced expression of Bcl-2 did not restore the number of NKT cells in IL-15 KO mice. As BrdU incorporation studies have shown that peripheral NKT cells are slowly dividing in an IL-15-dependent manner (46), the primary role of IL-15 in the homeostasis of these cells may be to provide proliferation signals rather than survival signals.…”

Section: Discussionmentioning

confidence: 99%

Enforced Expression of Bcl-2 Partially Restores Cell Numbers but Not Functions of TCRγδ Intestinal Intraepithelial T Lymphocytes in IL-15-Deficient Mice

Nakazato

Yamada

Yajima

et al. 2007

IL-15 knockout (KO) mice have severely reduced numbers of TCRγδ intestinal intraepithelial T lymphocytes (i-IEL), suggesting requirements of IL-15 signaling in the development or maintenance of i-IEL. To determine an involvement of survival signals via Bcl-2 in IL-15-mediated homeostasis of TCRγδ i-IEL, we introduced a bcl-2 transgene into IL-15 KO mice. In situ apoptosis of TCRγδ i-IEL was decreased in Bcl-2 transgenic (Tg) × IL-15 KO mice compared with IL-15 KO mice. The enforced expression of Bcl-2 partially restored the numbers of TCRγδ i-IEL in IL-15 KO mice. However, effector functions of TCRγδ i-IEL, including cytokine production and cytotoxic activity, were not recovered in Bcl-2 Tg × IL-15 KO mice. Importantly, TCRγδ i-IEL in Bcl-2 Tg × IL-15 KO mice expressed a reduced level of eomesodermin, a transcription factor critical for effector functions of NK cells and CD8+ T cells. Similar to the case of TCRγδ i-IEL, enforced expression of Bcl-2 restored the numbers but not the functions of NK cells in IL-15 KO mice. These results suggest that Bcl-2-mediated survival signal is involved in the IL-15-mediated homeostasis of TCRγδ i-IEL and NK cells, but other signals from IL-15 are critical for inducing transcription factors, such as eomesodermin for their effector functions.

“…In contrast, lack of homeostatic proliferation in double-deficient IL-7 Ϫ/Ϫ IL-15 Ϫ/Ϫ mice, as opposed to normal expansion in single-deficient (IL-7 Ϫ/Ϫ or IL-15 Ϫ/Ϫ ) mice and in IL-7 Ϫ/Ϫ IL-15 Ϫ/Ϫ mice treated with rIL-7, suggested that ␥␦ T cell homeostatic expansion requires either IL-7 (like most ␣␤ T cells) or IL-15 (like memory CD8 ϩ ␣␤ T cells). Other examples of homeostatic proliferation inhibition among functionally different lymphocyte subsets, such as NK, NKT, and memory CD8 ϩ ␣␤ T cells have also been interpreted as reflecting overlapping cytokine requirements (13). Thus, whereas inhibition of ␥␦ T cell homeostatic expansion by ␣␤ T cells is consistent with their consumption of IL-7 and IL-15, lack of inhibition by the IL-15-dependent NK cells is likely due to the small number of NK cells, to the fact that ␥␦ T cells can use IL-7 when IL-15 is not available, or to different localization of ␥␦ and NK cells.…”

Section: Discussionmentioning

confidence: 99%

“…Similar approaches have been used to define the homeostatic requirements for NK cells, NKT cells, and B cells. For homeostatic expansion in lymphopenic mice, NK cells require IL-15 (12), NKT cells require IL-15 (and less IL-7) but not the Ag-presenting CD1d molecule (13), and B cells require Btk-mediated signals but not IL-7 (14).…”

Section: ␥␦ T Cell Homeostasis Is Controlled By Il-7 and Il-15mentioning

confidence: 99%

γδ T Cell Homeostasis Is Controlled by IL-7 and IL-15 Together with Subset-Specific Factors

Baccalà

Witherden

Gonzalez-Quintial

et al. 2005

Self Cite

Among T cell subsets, γδ T cells uniquely display an Ag receptor-based tissue distribution, but what defines their preferential homing and homeostasis is unknown. To address this question, we studied the resources that control γδ T cell homeostasis in secondary lymphoid organs. We found that γδ and αβ T cells are controlled by partially overlapping resources, because acute homeostatic proliferation of γδ T cells was inhibited by an intact αβ T cell compartment, and both populations were dependent on IL-7 and IL-15. Significantly, to undergo acute homeostatic proliferation, γδ T cells also required their own depletion. Thus, γδ T cell homeostasis is maintained by trophic cytokines commonly used by other types of lymphoid cells, as well as by additional, as yet unidentified, γδ-specific factors.