Interleukin‐15 preferentially promotes the growth of intestinal intraepithelial lymphocytes bearing γδ T cell receptor in mice

Self Cite

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.

supporting

confidence: 86%

mentioning

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

Self Cite

“…IL-15 also plays important roles in proliferation, accumulation, and maintenance of NKT cells and a subset of ␥␦ T cells (18,22,23). The results of the present study revealed that the numbers of NKT cells and ␥␦ T cells were remarkably increased in WT mice after BCG infection (data not shown).…”

Section: Discussionmentioning

confidence: 47%

“…IL-15 has been reported to stimulate NK cells and TCR␥␦ intestinal intraepithelial lymphocytes to produce IFN-␥ and enhance their cytotoxicity (17,18). Furthermore, IL-15 has an important function in the proliferation and survival of memory-phenotype CD8 ϩ T cells.…”

Section: Impaired Protection Against Mycobacterium Bovismentioning

confidence: 99%

Impaired Protection against Mycobacterium bovis Bacillus Calmette-Guérin Infection in IL-15-Deficient Mice

Saito

Yajima

Kumabe

et al. 2006

Self Cite

To investigate the potential role of endogenous IL-15 in mycobacterial infection, we examined protective immunity in IL-15-deficient (IL-15−/−) mice after infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG) or recombinant OVA-expressing BCG (rBCG-OVA). IL-15−/− mice exhibited an impaired protection in the lung on day 120 after BCG infection as assessed by bacterial growth. CD4+ Th1 response capable of producing IFN-γ was normally detected in spleen and lung of IL-15−/− mice on day 120 after infection. Although Ag-specific CD8 responses capable of producing IFN-γ and exhibiting cytotoxic activity were detected in the lung on day 21 after infection with rBCG-OVA, the responses were severely impaired on days 70 and 120 in IL-15−/− mice. The degree of proliferation of Ag-specific CD8+ T cells in IL-15−/− mice was similar to that in wild-type mice during the course of infection with rBCG-OVA, whereas sensitivity to apoptosis of Ag-specific CD8+ T cells significantly increased in IL-15−/− mice. These results suggest that IL-15 plays an important role in the development of long-lasting protective immunity to BCG infection via sustaining CD8 responses in the lung.

“…Since the discovery that intestinal epithelial cells (i-EC) 3 can produce IL-15 in mice, rats, and humans (9,10), a focus of research in mucosal immunity has been to elucidate the possible role of IL-15 in the mucosal interaction between i-EC and intestinal intraepithelial lymphocytes (i-IEL). Upon infection with Listeria monocytogenes, i-EC in rats begin to produce IL-15, which in turn stimulates i-IEL to produce IFN-␥ (11).…”

Section: Il-15 and Il-15 Receptormentioning

confidence: 99%

IL-15 and IL-15 Receptor Selectively Regulate Differentiation of Common Mucosal Immune System-Independent B-1 Cells for IgA Responses

Hiroi

Yanagita

Ohta

et al. 2000

We show in this report a new regulatory role for IL-15 and IL-15R in the development of B-1 cells and their differentiation into IgA-producing cells. Mucosal IgA levels were found to be inhibited by anti-IL-15 mAb treatment in vivo, but enhanced by administration of rIL-15, while serum IgA levels remained unaffected. Mucosal B-1 cells preferentially proliferated in response to IL-15 in vitro. When mucosal B-1 and B-2 cells were separated into surface (s)IgM+sIgA− and sIgM−sIgA+ fractions, IL-15R-specific mRNA was found to be predominant in both sIgM+sIgA− and sIgM−sIgA+ B-1 cells at a much higher level than B-2 cells. Further, incubation of these different subsets of B-1 and B-2 cells with IL-15 resulted in greater enhancement of the corresponding receptor expression by B-1 subset when compared with B-2 fraction. Interestingly, de novo isolated sIgM+sIgA− B-1, but not sIgM+sIgA− B-2, cells were already class-switched cells because the germline Cα transcript was detected and was then further enhanced by IL-15. IL-15 also supported differentiation of both sIgM+sIgA− and sIgM−sIgA+ B-1 cells into IgA-producing cells. Taken together, these findings suggest that IL-15 is a critically important cytokine for the differentiation of both sIgM+,IgA− and sIgM−sIgA+ B-1 cells expressing IL-15R into IgA-producing cells in mucosal tissues.