Regulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question

doi:10.1016/S1471-4906(00)01798-1

Trends in Immunology

Volume 22, Issue 1, 1 January 2001, Pages 21-26

https://doi.org/10.1016/S1471-4906(00)01798-1 Get rights and content

Abstract

T-cell resistance against apoptosis contributes to inappropriate T-cell accumulation and the perpetuation of chronic mucosal inflammation in inflammatory bowel diseases (IBDs). Anti-interleukin-12 (IL-12) and anti-IL-6 receptor antibodies suppress colitis activity by the induction of T-cell apoptosis. These findings have important implications for the design of effective treatment regimens in IBD.

Section snippets

Regulation of apoptosis of lamina propria T cells via active and passive mechanisms

Immune responses in the mucosa are frequently characterized by major expansions of antigen-specific T cells that have potent effector function 1., 8., 9., 10.. Although this might be important for host defense, it might also lead to effector cell populations with substantial autoreactivity and the capacity to cause mucosal inflammation. To deal with this latter possibility, the mucosal immune system has evolved several strategies for the control of mucosal immune responses. Among these is the

Apoptosis of lamina propria CD4⁺ T cells in the normal and inflamed gut

As most T cells in the lamina propria (LP) express memory cell markers such as CD45RO (Ref. ³), the activation-induced cell death might be very important to downregulate effector cell function and cytokine production in the gut. Interestingly, memory T cells are known to express Fas constitutively at high levels ¹³. In the unstimulated state, (that is, prior to TCR stimulation), LP T cells exhibit increased susceptibility to Fas-mediated apoptosis as compared with unstimulated peripheral-blood

IL-12 and apoptosis

Administration of a neutralizing anti-IL-12 antibody to mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis, a T helper 1 (Th1) -mediated inflammation replete with cells producing large amounts of interferon-γ (IFN-γ), IL-12 and TNF-α, is followed after two days by the appearance of apoptotic (terminal deoxynucleotidyltransferase-mediated UTP end-labeling positive, TUNEL⁺) CD4⁺ cells at the site of inflammation in the colon ⁸. This induction of T-cell apoptosis is followed by the

Concluding remarks

Apoptosis of LP T cells appears to be critical in the downregulation of the mucosal immune response and in the elimination of reactive clones. Whereas normal LP T cells exhibit an enhanced susceptibility to Fas-mediated apoptosis ¹⁶, Crohn's disease is associated with a resistance of LP T cells against multiple apoptotic pathways 6., 18., 19.. Such defective apoptosis may be a key factor for inappropriate T-cell accumulation and in the perpetuation of chronic mucosal inflammation in IBD (Fig. 3

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Trends in Immunology

OpinionRegulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question

Abstract

Section snippets

Regulation of apoptosis of lamina propria T cells via active and passive mechanisms

Apoptosis of lamina propria CD4+ T cells in the normal and inflamed gut

IL-12 and apoptosis

Concluding remarks

Experimental models of inflammatory bowel disease

Gastroenterology

Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation

Immunol. Today

Antibodies to IL-12 abrogate established experimental colitis in mice

J. Exp. Med.

T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/Signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon gamma expression by T cells

J. Exp. Med.

Blockade of IL-6 trans-signaling suppresses T cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn's disease and experimental colitis in vivo

Nat. Med.

IL-6 is required for the development of Th1 cell-mediated murine colitis

J. Immunol.

Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice

Gastroenterology

Regulatory T cells and inflammatory bowel disease

Immunol. Today

Recent developments in the immunology of inflammatory bowel disease

Scand. J. Immunol.

Apoptosis signaling in lymphocytes

Curr. Opin. Immunol.

Induction of apoptosis in mature T cells by tumour necrosis factor

Nature

Mature T lymphocyte apoptosis-immune regulation in a dynamic and unpredictable antigenic environment

Annu. Rev. Immunol.

Two CD95 (APO-1/Fas) signaling pathways

EMBO J.

Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1

Nature

Stimulated human lamina propria T cells manifest enhanced Fas-mediated apoptosis

J. Clin. Invest.

Definition of a lamina propria T cell responsive state. Enhanced cytokine responsiveness of T cells stimulated through the CD2 pathway

J. Immunol.

Lamina propria T cells in Crohn's disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis

Gastroenterology

Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance

J. Immunol.

Opinion
Regulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question

Apoptosis of lamina propria CD4⁺ T cells in the normal and inflamed gut