Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4+ T cell immunity

Abstract

The gut mucosa hosts large numbers of activated lymphocytes, exposed to stimuli from diet, microbiota and pathogens. Although CD4+ T cells are crucial for defense, intestinal homeostasis precludes exaggerated response towards luminal contents, harmful or not. We investigated mechanisms used by CD4+ T cells to avoid excessive activation within the intestine. Using genetic tools to label and interfere with T cell development transcription factors we show that CD4+ T cells acquired CD8-lineage transcription factor Runx3 while losing CD4-lineage transcription factor ThPOK along with their TH17 differentiation and colitogenic potential, in a transforming growth factor-β (TGF-β) and retinoic-acid-dependent manner. These results show a remarkable plasticity in the CD4+ T cell lineage that allows chronic exposure to luminal antigens without pathological inflammation.

Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells

“…The latter result could be due to the enhancing effect of Runx3 on the expression of IL-17A, similar to that observed in certain subsets of T cells. 50,51 The above data confirmed that, in the absence of Runx3, cytokine production was not markedly altered in vivo and in vitro, whereas in the absence of both Runx3 and ThPok, the cytokine profile of iNKT cells was affected, indicating that Runx3 is involved in the function of iNKT cells in ThPok-deficient mice.…”

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…This direct regulation is evident in a transgenic diabetes mouse model in which loss of TGF-b signaling in activated diabetogenic CD4 þ T cells, but not Treg cells, induces disease (Ishigame et al 2013b). In addition, in the intestine, TGF-b signaling limits tissue damage by diverting pathogenic CD4 þ T cells to a nonpathogenic phenotype (Reis et al 2013). Moreover, the control of autoreactive T cells by Treg cells in vivo may also occur through TGF-b signaling.…”

Murine Splenic CD4+ T Cells, Induced by Innate Immune Cell Interactions and Secreted Factors, Develop Antileukemia Cytotoxicity

“…This phenomenon has been observed mostly in chronic infections (21), but there is growing recognition of this population of cells in malignancy (22), including their detection in peripheral blood of patients with B-cell chronic lymphocytic leukemia (23). Two recent studies have demonstrated CD4 þ T-cell plasticity (1,2) under steady state in the gut. Our data showed that CD4 þ T cells with the capacity to activate a cytotoxic program also reside in the spleen.…”

“…70Z/3 was stably transduced with a fusion form of the IL12 cDNA using a lentivirus vector as previously reported and authenticated by sequence matching (4). The IL12-transduced clone LV12.2, the parent 70Z/3 line, and the NKT cell line C1498 (obtained from the ATCC) were maintained in RPMI-1640 with 5% heat-inactivated FBS (Gibco), 10 mmol/L HEPES, 100 mg/mL penicillin-streptomycin or kanamycin, and 5.5 Â 10 À5 mol/L b-mercaptoethanol in a humidified atmosphere at 37 C in 5% CO 2 . The IFNg-resistant cell line LV12.2-R ("R" denotes the resistant line) was produced by culturing cells in increasing amounts of IFNg for a period of nearly 2 months until the concentration of IFNg was equal to 10 ng/mL.…”

“…CD4 þ CTLs were often considered as a type of overactivated Th1 cell until two companion articles revealed a unique transcription factor signature for CD4 þ CTLs: Runx3 expression resulted in diminished ThPOK expression and de-repression of the CD8 þ T cell-associated cytotoxic program in mature, stimulated CD4 þ T cells (1,2). These studies used the gut as their model tissue and suggested that it is the inflammatory milieu of this unique environment that gives rise to such cells.…”