Involvement of OX40-OX40L interactions in the intestinal manifestations of the murine acute graft-versus-host disease

364

339

The costimulatory receptor OX40 has recently been shown to be involved in primary CD4 responses to several defined Ags. However, to date there has been little information regarding the mechanism of action of OX40, such as whether it regulates T cell numbers, reactivity, or both, and whether it contributes to induction of long-term T cell responses. With an agonist Ab to OX40, and by tracking Ag-specific TCR transgenic T cells in vivo, we show that ligation of OX40 induces clonal expansion and survival of CD4 cells during primary responses, and results in the accumulation of greater numbers of memory cells with time. Significantly, OX40-deficient T cells, from mice generated by gene targeting, secrete IL-2 and proliferate normally during the initial period of activation, but cannot sustain this during the latter phases of the primary response, exhibiting decreased survival over time. Mice lacking OX40 develop only low frequencies of Ag-specific CD4 cells late in primary responses in vivo and generate dramatically lower frequencies of surviving memory cells. These results demonstrate that OX40-OX40L interactions control primary T cell expansion and the ability to retain high numbers of Ag-specific T cells. In this way, OX40 signals promote survival of greater numbers of T cells with time and control the size of the memory T cell pool.

Section: Discussionmentioning

confidence: 71%

“…Blocking OX40 reduced gut inflammation in colitis (30), suppressed paralysis in EAE (19), and prevented hyperplasia in GVHD (31). An initial study of OX40-deficient animals showed that they mounted normal responses to Leishmania and Nippostrongylus in vivo, but T cells from these mice proliferated poorly in vitro (22).…”

mentioning

confidence: 99%

The OX40 Costimulatory Receptor Determines the Development of CD4 Memory by Regulating Primary Clonal Expansion

Gramaglia

Jember

Pippig

et al. 2000

364

339

“…Furthermore, OX40 stimulation has been reported to prevent peripheral tolerance of CD4 ϩ T cells (25), suggesting a possible involvement of the OX40/OX40L system in regulating autoimmunity. Indeed, expression of OX40 and/or OX40L has been demonstrated in the tissues of several immune disorders such as experimental allergic encephalitis (24, 26 -28), experimental inflammatory bowel diseases (IBDs) (29,30), graft-vs-host disease (31)(32)(33), human proliferative lupus nephritis (34), rheumatoid arthritis (35,36), human IBD (37,38), human inflammatory muscle diseases (39), and in thymoma of patients with myasthenia gravis (40). In vivo blockade of OX40/ OX40L interaction has been described not only to suppress ongoing experimental allergic encephalitis (28) and graft-vs-host disease (32,41), but also to ameliorate ongoing colitis in murine models of IBD (29,30), asthma (42), and collagen-induced arthritis (35).…”

mentioning

confidence: 99%

Constitutive OX40/OX40 Ligand Interaction Induces Autoimmune-Like Diseases

Murata

Nose

Ndhlovu

et al. 2002

112

The interaction between OX40 and OX40 ligand (OX40L) is suggested to provide T cells with an effective costimulatory signals during T cell-APC interaction. To examine the in vivo effect of constitutive OX40/OX40L interaction during immune regulation, we report the establishment of OX40L-transgenic (OX40L-Tg) mice that constitutively express OX40L on T cells. Markedly elevated numbers of effector memory CD4+ T cells, but not CD8+ T cells, were observed in the secondary lymphoid organs of OX40L-Tg mice. Upon immunization with keyhole limpet hemocyanin in the absence of adjuvant, profound T cell proliferative responses and cytokine productions were seen in the OX40L-Tg mice as compared with wild-type mice. Furthermore, in OX40L-Tg mice administrated with superantigen, this constitutive OX40/OX40L interaction on CD4+ T cells completely prevented normal in vivo clonal T cell deletion. Interestingly, OX40L-Tg mice on the C57BL/6 background spontaneously developed interstitial pneumonia and inflammatory bowel disease that was accompanied with a significant production of anti-DNA Ab in the sera. Surprisingly, these diseases were not evident on the OX40L-Tg mice on the BALB/c strain. However, such inflammatory diseases were successfully reproducible in recombination-activating gene (RAG)2-deficient mice upon transfer of OX40L-Tg CD4+ T cells. Blockade of OX40/OX40L interaction in the recipient RAG2-deficient mice completely prevented disease development. The present results orchestrated in this study indicate that OX40/OX40L interaction may be a vital link in our understanding of T cell-mediated organ-specific autoimmunity.

“…Thus, CD134 ϩ T cells are found in inflammatory lesions, and blocking CD134-CD134L interactions via administration of a CD134-Ig fusion protein led to amelioration of experimental autoimmune encephalomyelitis (EAE) (30) and of intestinal inflammation (30,39,40). Although these studies clearly show that CD134-CD134L interactions play a role in T cell-mediated immune pathology, they do not reveal precisely how.…”

mentioning

confidence: 99%

CD134L Expression on Dendritic Cells in the Mesenteric Lymph Nodes Drives Colitis in T Cell-Restored SCID Mice

Malmström

Shipton

Singh

et al. 2001

188

143

Transfer of CD45RBhigh CD4+ T cells to immune-deficient mice in the absence of regulatory T cells leads to a Th1-mediated colitis. In this study, we show that intestinal inflammation is characterized by a 15-fold increase in the number of CD134L+ (OX40L+)-activated DC in the mesenteric lymph nodes (MLNs) compared with BALB/c mice. This was important functionally, as administration of an anti-CD134L mAb inhibited the proliferation of T cells in the MLNs as well as their expression of the gut-homing integrin α4β7. Most importantly, the anti-CD134L mAb completely blocked development of colitis. Surprisingly, CD134L was found to be expressed by a proportion of dendritic cells (DC) in the MLNs of unreconstituted SCID mice, suggesting that CD134L can be induced on DC in the absence of T cell-derived signals. These results indicate that some DC in the MLNs of SCID mice express an activated phenotype and that CD134L expression by these cells is involved in the development of colitis induced by T cell transfer. Accumulation of CD134L+ DC was inhibited by cotransfer of regulatory T cells, suggesting that inhibition of the accumulation of activated DC is one mechanism by which these cells prevent immune pathology.