c-Myc controls the development of CD8αα TCRαβ intestinal intraepithelial lymphocytes from thymic precursors by regulating IL-15–dependent survival

Blood ◽  
2010 ◽  
Vol 115 (22) ◽  
pp. 4431-4438 ◽  
Author(s):  
Wei Jiang ◽  
Isabel Ferrero ◽  
Elisa Laurenti ◽  
Andreas Trumpp ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
Large Population ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Receptor Expression ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Wide Range ◽  
Interleukin 15 ◽  
Secondary Lymphoid Organs ◽  
Deficient Mice

Abstract The murine gut epithelium contains a large population of thymus-derived intraepithelial lymphocytes (IELs), including both conventional CD4+ and CD8αβ+ T cells (expressing T-cell receptor αβ [TCRαβ]) and unconventional CD8αα+ T cells (expressing either TCRαβ or TCRγδ). Whereas conventional IELs are widely accepted to arise from recirculation of activated CD4+ and CD8αβ+ T cells from the secondary lymphoid organs to the gut, the origin and developmental pathway of unconventional CD8αα IELs remain controversial. We show here that CD4-Cre-mediated inactivation of c-Myc, a broadly expressed transcription factor with a wide range of biologic activities, selectively impairs the development of CD8αα TCRαβ IELs. In the absence of c-Myc, CD4− CD8− TCRαβ+ thymic precursors of CD8αα TCRαβ IELs are present but fail to develop on adoptive transfer in immunoincompetent hosts. Residual c-Myc–deficient CD8αα TCRαβ IEL display reduced proliferation and increased apoptosis, which correlate with significantly decreased expression of interleukin-15 receptor subunits and lower levels of the antiapoptotic protein Bcl-2. Transgenic overexpression of human BCL-2 resulted in a pronounced rescue of CD8αα TCRαβ IEL in c-Myc–deficient mice. Taken together, our data support a model in which c-Myc controls the development of CD8αα TCRαβ IELs from thymic precursors by regulating interleukin-15 receptor expression and consequently Bcl-2–dependent survival.

scholarly journals Interleukin-15 May Be Responsible for Early Activation of Intestinal Intraepithelial Lymphocytes after Oral Infection with Listeria monocytogenes in Rats

1998 ◽  
Vol 66 (12) ◽  
pp. 5677-5683 ◽  
Author(s):  
Kenji Hirose ◽  
Hirohiko Suzuki ◽  
Hitoshi Nishimura ◽  
Akio Mitani ◽  
Junji Washizu ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Oral Infection ◽  
Epithelial Cell Line ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Interleukin 15 ◽  
Ifn Γ

ABSTRACT Exogenous interleukin-15 (IL-15) stimulates intestinal intraepithelial lymphocytes (i-IEL) from mice to proliferate and produce gamma interferon (IFN-γ) in vitro. To determine whether endogenous IL-15 is involved in activation of i-IEL during intestinal infection, we examined IL-15 synthesis by intestinal epithelial cells (i-EC) after infection with Listeria monocytogenes in rats. In in vitro experiments, invasion of L. monocytogenes into IEC-6 cells, a rat small intestine epithelial cell line, evidently induced IL-15 mRNA expression coincident with nuclear factor κB (NF-κB) activation, which is essential for IL-15 gene expression. IL-15 synthesis was detected in rat i-EC on day 1 after an oral inoculation of L. monocytogenes in vivo. The numbers of T-cell receptor (TCR) γδ+ T cells, NKR.P1+cells, and CD3+ CD8+ αα cells in i-IEL were significantly increased on day 1 after oral infection. The i-IEL from infected rats produced larger amounts of IFN-γ upon stimulation with immobilized anti-TCR γδ or anti-NKR.P1 monoclonal antibodies. These results suggest that IL-15 produced by i-EC may stimulate significant fractions of i-IEL to produce IFN-γ at an early phase of oral infection with L. monocytogenes.

scholarly journals T cells with gamma/delta T cell receptors (TCR) of intestinal type are preferentially expanded in TCR-alpha-deficient lpr mice.

1995 ◽  
Vol 182 (1) ◽  
pp. 233-241 ◽  
Author(s):  
D P Hughes ◽  
A Hayday ◽  
J E Craft ◽  
M J Owen ◽  
I N Crispe
Keyword(s):  
T Cells ◽  
T Cell ◽  
Variable Region ◽  
Fold Increase ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Gamma Delta ◽  
Activation Induced Cell Death ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Gamma Delta T Cell

Fas-mediated apoptosis is essential for activation-induced cell death of alpha/beta T cells, but it is not clear what role, if any, it plays in regulating other components of the immune system. To study the role of Fas in gamma/delta T cell development, Fas-deficient lpr mice were bred with T cell receptor alpha gene-ablated (TCR-alpha-/-) mice to generate mice deficient in one or both genes. The TCR-alpha-/-, lpr/lpr mice had a nearly 10-fold increase in total lymph node cell (LNC) number compared with Fas-intact TCR-alpha-/- mice, because of expansion of TCR-gamma/delta+ and TCR-beta+ cells. In Fas-intact TCR-alpha-/- mice, approximately one third of the LNCs expressed TCR-gamma/delta. These were evenly divided between the CD4-, CD8-alpha+ and the CD4-, CD8- subsets, and rarely expressed the B220 epitope of CD45. In contrast, in TCR-alpha-/-, lpr/lpr mice, TCR-gamma/delta+ cells comprised half of the LNCs and were primarily CD4-, CD8-, and B220+. Moreover, Fas deficiency in TCR-alpha-/- mice caused a preferential expansion of gamma/delta T cells expressing variable region genes characteristic of intestinal intraepithelial lymphocytes. These results demonstrate a role for Fas in regulating the gamma/delta T cell contribution to peripheral lymph nodes. This mechanism may be most important in limiting the access of activated intestinal intraepithelial lymphocytes to the peripheral lymphoid system.

scholarly journals Intestinal intraepithelial lymphocytes include precursors committed to the T cell receptor αβ lineage

1998 ◽  
Vol 95 (16) ◽  
pp. 9459-9464 ◽  
Author(s):  
Stephanie T. Page ◽  
Lisa Y. Bogatzki ◽  
Jessica A. Hamerman ◽  
Claire H. Sweenie ◽  
Philip J. Hogarth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Nude Mice ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Tcr Signaling ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Cell Commitment

The majority of T cells develop in the thymus and exhibit well characterized phenotypic changes associated with their maturation. Previous analysis of intestinal intraepithelial lymphocytes (IEL) from nude mice and a variety of experimentally manipulated models led to the view that at least a portion of these cells represent a distinct T cell population that matures extrathymically. The IEL that are postulated to mature within the intestine include both T cell receptor (TCR) αβ- and γδ-bearing subpopulations. They can be distinguished from conventional thymically derived T cells in that they express an unusual coreceptor, a CD8α homodimer. In addition, they can utilize the Fc receptor γ-chain in place of the CD3-associated ζ-chain for TCR signaling and their maturation depends on the interleukin 2 receptor β-chain. Moreover, TCRαβ+CD8αα+ IEL are not subject to conventional thymic selection processes. To determine whether CD3−CD8αα+ IEL represent precursors of T cells developing extrathymically, we examined IEL from knockout mice lacking the recombination activating gene-1 (rag-1), CD3ɛ, or both Lck and Fyn, in which thymic T cell development is arrested. CD3−CD8αα+CD16+ IEL from all three mutant strains, as well as from nude mice, included cells that express pre-TCRα transcripts, a marker of T cell commitment. These IEL from lck−/−fyn−/− animals exhibited TCR β-gene rearrangement. However, CD3−CD8αα+CD16+ IEL from ɛ-deficient mice had not undergone Dβ-Jβ joining, despite normal rearrangement at the TCRβ locus in thymocytes from these animals. These results revealed another distinction between thymocytes and IEL, and suggested an unexpectedly early role for CD3ɛ in IEL maturation.

scholarly journals Development of Cd8α/α and Cd8α/β T Cells in Major Histocompatibility Complex Class I–Deficient Mice

1999 ◽  
Vol 190 (6) ◽  
pp. 881-884 ◽  
Author(s):  
Gobardhan Das ◽  
Charles A. Janeway
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Intraepithelial Lymphocytes ◽  
Class I ◽  
Major Histocompatibility ◽  
Double Knockout ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Histocompatibility Complex ◽  
Deficient Mice

Peripheral CD8+ T cells mainly use CD8α/β, and their development is mainly dependent on the major histocompatibility complex (MHC) class I proteins Kb and Db in H-2b mice. In this report, we have shown that the development of CD8α/β TCR-α/β cells in lymphoid organs as well as in intestinal intraepithelial lymphocytes (iIELs) is dependent on the MHC class I Kb and Db proteins. In contrast, TCR-α/β CD8α/α cells are found mainly in iIELs, and their numbers are unaffected in KbDb double knockout mice. Most of the TCR-γ/δ cells in the iIELs also bear CD8α/α, and they are also unaffected in KbDb −/− mice. In β2-microglobulin (β2m)-deficient mice, all of the TCR-α/β CD8α/α and CD8α/β T cells disappear, but TCR-γ/δ cells are unaffected by the absence of β2m.

scholarly journals Development of Intestinal Intraepithelial Lymphocytes, NK Cells, and NK 1.1+ T Cells in CD45-Deficient Mice

2001 ◽  
Vol 166 (10) ◽  
pp. 6066-6073 ◽  
Author(s):  
Steven M. Martin ◽  
Indira K. Mehta ◽  
Wayne M. Yokoyama ◽  
Matthew L. Thomas ◽  
Robin G. Lorenz
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Intraepithelial Lymphocytes ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Deficient Mice

scholarly journals The life span of naive alpha/beta T cells in secondary lymphoid organs.

1993 ◽  
Vol 177 (4) ◽  
pp. 891-896 ◽  
Author(s):  
H von Boehmer ◽  
K Hafen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Life Span ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Lymphoid Organs ◽  
Alpha Beta ◽  
Secondary Lymphoid Organs ◽  
Deficient Mice

We have determined the life span of naive CD4-8+ T cells in T cell receptor transgenic mice. We find that such cells do not divide in secondary lymphoid organs in both normal euthymic mice and T cell-deficient mice. By both continuous labeling and by chasing pulse-labeled cells, we find that the minimum life span of the naive T cells is in the order of 8 wk.

scholarly journals CD8α-Deficient Mice Are Highly Susceptible to 5-Fluorouracil-Induced Lethality

2002 ◽  
Vol 9 (3) ◽  
pp. 550-557 ◽  
Author(s):  
Naoto Itoh ◽  
Hitoshi Nishimura ◽  
Tetsuya Matsuguchi ◽  
Toshiki Yajima ◽  
Yasuji Mokuno ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
Homologous Recombination ◽  
T Cell Receptor ◽  
Intestinal Microflora ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Significant Protection ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Deficient Mice

ABSTRACT Intestinal intraepithelial lymphocytes (i-IEL) expressing CD8α are located in the intestine and may confer protection against invasion of intestinal microflora. We found that mice rendered deficient in CD8α molecules by homologous recombination were susceptible to 5-fluorouracil (5-FU)-induced lethality accompanied by translocation of members of the enterobacteria. The number of i-IEL was greatly reduced on day 6 after 5-FU administration in both CD8α+/− mice and CD8α−/− mice, whereas the recovery of the level of i-IEL thereafter was significantly impaired in CD8α−/− mice compared with that in CD8α+/− mice. The ability of i-IEL to produce gamma interferon in response to immobilized T-cell receptor (TCR) αβ or TCR γδ monoclonal antibodies was significantly lower in CD8α−/− mice than in CD8α+/− mice. Transfer of CD8+ i-IEL conferred significant protection against 5-FU-induced lethality in CD8α−/− mice. The results suggest that CD8+ i-IEL play an important role in protection against 5-FU-induced lethality with translocation of Enterobacteriaceae.

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