Damon J. Tumes

The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-β and suppresses T(H)2 differentiation.

Sox4 is a transcription factor that regulates various developmental processes. Here we show that Sox4 was induced by TGF-β and negatively regulated the transcription factor GATA-3, the master regulator of function of T helper type 2 (TH2) cells, by two distinct mechanisms. First, Sox4 bound directly to GATA-3, preventing its binding to GATA-3 consensus DNA sequences. Second, Sox4 bound to the promoter region of the gene encoding interleukin 5 (IL-5), a TH2 cytokine, and prevented binding of GATA-3 to this promoter. TH2 cell–driven airway inflammation was modulated by alterations in Sox4 expression. Thus, Sox4 acted as a downstream target of TGF-β to inhibit GATA-3 function, TH2 differentiation and TH2 cell–mediated inflammation.

The Interleukin-33-p38 Kinase Axis Confers Memory T Helper 2 Cell Pathogenicity in the Airway

Memory CD4(+) T helper (Th) cells provide long-term protection against pathogens and are essential for the development of vaccines; however, some antigen-specific memory Th cells also drive immune-related pathology, including asthma. The mechanisms regulating the pathogenicity of memory Th cells remain poorly understood. We found that interleukin-33 (IL-33)-ST2 signals selectively licensed memory Th2 cells to induce allergic airway inflammation via production of IL-5 and that the p38 MAP kinase pathway was a central downstream target of IL-33-ST2 in memory Th2 cells. In addition, we found that IL-33 induced upregulation of IL-5 by memory CD4(+) T cells isolated from nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, IL-33-ST2-p38 signaling appears to directly instruct pathogenic memory Th2 cells to produce IL-5 and induce eosinophilic inflammation.

Eomesodermin Controls Interleukin-5 Production in Memory T Helper 2 Cells through Inhibition of Activity of the Transcription Factor GATA3

The regulation of memory CD4(+) helper T (Th) cell function, such as polarized cytokine production, remains unclear. Here we show that memory T helper 2 (Th2) cells are divided into four subpopulations by CD62L and CXCR3 expression. All four subpopulations produced interleukin-4 (IL-4) and IL-13, whereas only the CD62L(lo)CXCR3(lo) population produced IL-5 accompanied by increased H3-K4 methylation at the Il5 gene locus. The transcription factor Eomesodermin (encoded by Eomes) was highly expressed in memory Th2 cells, whereas its expression was selectively downregulated in the IL-5-producing cells. Il5 expression was enhanced in Eomes-deficient cells, and Eomesodermin was shown to interact with the transcription factor GATA3, preventing GATA3 binding to the Il5 promoter. Memory Th2 cell-dependent airway inflammation was attenuated in the absence of the CD62L(lo)CXCR3(lo) population but was enhanced by Eomes-deficient memory Th2 cells. Thus, IL-5 production in memory Th2 cells is regulated by Eomesodermin via the inhibition of GATA3 activity.

Type II membrane protein CD69 regulates the formation of resting T-helper memory

Memory T-helper (Th) lymphocytes are crucial for the maintenance of acquired immunity to eliminate infectious pathogens. We have previously demonstrated that most memory Th lymphocytes reside and rest on stromal niches of the bone marrow (BM). Little is known, however, regarding the molecular basis for the generation and maintenance of BM memory Th lymphocytes. Here we show that CD69-deficient effector CD4 T lymphocytes fail to relocate into and persist in the BM and therefore to differentiate into memory cells. Consequently, CD69-deficient CD4 T cells fail to facilitate the production of high-affinity antibodies and the generation of BM long-lived plasma cells in the late phase of immune responses. Thus, CD69 is critical for the generation and maintenance of professional memory Th lymphocytes, which can efficiently help humoral immunity in the late phase. The deficit of immunological memory in CD69-deficient mice also highlights the essential role of BM for the establishment of Th memory.

Th2 Cells in Health and Disease

Helper T (Th) cell subsets direct immune responses by producing signature cytokines. Th2 cells produce IL-4, IL-5, and IL-13, which are important in humoral immunity and protection from helminth infection and are central to the pathogenesis of many allergic inflammatory diseases. Molecular analysis of Th2 cell differentiation and maintenance of function has led to recent discoveries that have refined our understanding of Th2 cell biology. Epigenetic regulation of Gata3 expression by chromatin remodeling complexes such as Polycomb and Trithorax is crucial for maintaining Th2 cell identity. In the context of allergic diseases, memory-type pathogenic Th2 cells have been identified in both mice and humans. To better understand these disease-driving cell populations, we have developed a model called the pathogenic Th population disease induction model. The concept of defined subsets of pathogenic Th cells may spur new, effective strategies for treating intractable chronic inflammatory disorders.

Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity

GATA binding protein 3 (Gata3) is a GATA family transcription factor that controls differentiation of naïve CD4 T cells into T helper 2 (Th2) cells. However, it is unknown how Gata3 simultaneously activates Th2-specific genes while repressing those of other Th lineages. Here we show that chromodomain helicase DNA-binding protein 4 (Chd4) forms a complex with Gata3 in Th2 cells that both activates Th2 cytokine transcription and represses the Th1 cytokine IFN-γ. We define a Gata3/Chd4/p300 transcriptional activation complex at the Th2 cytokine loci and a Gata3/Chd4–nucleosome remodeling histone deacetylase repression complex at the Tbx21 locus in Th2 cells. We also demonstrate a physiological role for Chd4 in Th2-dependent inflammation in an in vivo model of asthmatic inflammation. Thus, Gata3/Chd4 forms functionally distinct complexes, which mediate both positive and negative gene regulation to facilitate Th2 cell differentiation.

Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1

Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity-associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat-fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca) as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo. ACC1 modulates the DNA binding of RORγt to target genes in differentiating Th17 cells. In addition, we found a strong correlation between IL-17A-producing CD45RO(+)CD4 T cells and the expression of ACACA in obese subjects. Thus, ACC1 confers the appropriate function of RORγt through fatty acid synthesis and regulates the obesity-related pathology of Th17 cells.

Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation

Significance A substantial proportion of people have intractable chronic allergic diseases for which no curative treatment exists. A clear understanding of how these allergic diseases develop and persist is lacking. Here, unique ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue were found to be formed during chronic airway inflammation, and were critical in persistent inflammation. In addition, we identified a Thy1+IL-7+IL-33+ subset of lymphatic endothelial cells (LECs) that support the maintenance of memory-type pathogenic T helper 2 (Tpath2) cells. A similar population of IL-7+IL-33+ LECs was found in nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, we revealed that Thy1+IL-7–producing LECs control chronic allergic airway inflammation by supporting memory-type Tpath2 cells in human and mouse systems. Memory CD4+ T helper (Th) cells are central to long-term protection against pathogens, but they can also be pathogenic and drive chronic inflammatory disorders. How these pathogenic memory Th cells are maintained, particularly at sites of local inflammation, remains unclear. We found that ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue (iBALT) are formed during chronic allergic inflammation in the lung, and that memory-type pathogenic Th2 (Tpath2) cells capable of driving allergic inflammation are maintained within the iBALT structures. The maintenance of memory Th2 cells within iBALT is supported by Thy1+IL-7–producing lymphatic endothelial cells (LECs). The Thy1+IL-7–producing LECs express IL-33 and T-cell–attracting chemokines CCL21 and CCL19. Moreover, ectopic lymphoid structures consisting of memory CD4+ T cells and IL-7+IL-33+ LECs were found in nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, Thy1+IL-7–producing LECs control chronic allergic airway inflammation by providing a survival niche for memory-type Tpath2 cells.

Strain-dependent resistance to allergen-induced lung pathophysiology in mice correlates with rate of apoptosis of lung-derived eosinophils

Although exposed to similar allergic and environmental stimuli, not all humans develop asthma. Similarly, mouse strains vary in the degree of pathophysiology seen following induction of experimental asthma. Three mouse strains (CBA/Ca, BALB/c, and C57BL/6) were used to determine if the extent and duration of inflammation influenced the degree of lung tissue damage in an OVA‐induced allergic asthma model. Airways obstruction, leukocyte infiltration, edema, eosinophil accumulation, and degranulation were less severe in wild‐type (wt) CBA/Ca mice than wt BALB/c and C57BL/6 mice. F1 hybrids of CBA/Ca mice crossed with BALB/c or C57BL/6 mice had bronchoalveolar lavage leukocyte (BAL) and cell‐free protein profiles similar to those of the respective disease‐susceptible parental strain. IL‐5 transgene expression on each of the three genetic backgrounds accentuated the difference between CBA/Ca and the other two strains. Importantly, even when overexpressing IL‐5, CBA/Ca mice did not develop substantial airways obstruction. Eosinophils recovered from the airways of allergic wt and IL‐5 transgenic (Tg) CBA/Ca mice entered apoptosis at a faster rate than eosinophils from the other parental strains and F1 hybrids. In contrast, eosinophils harvested from the peritoneal cavities of untreated CBA/Ca IL‐5 Tg mice had a relatively low rate of apoptosis in vitro. The CBA/Ca mouse strain is therefore relatively resistant to experimental asthma, and this may be a consequence of a propensity for apoptosis of eosinophils recruited into the allergic lung. Restricting survival of a key effector cell may thus limit pathogenesis in this experimental model and in humans.

Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells

To fulfil the bioenergetic requirements for increased cell size and clonal expansion, activated T cells reprogramme their metabolic signatures from energetically quiescent to activated. However, the molecular mechanisms and essential components controlling metabolic reprogramming in T cells are not well understood. Here, we show that the mTORC1–PPARγ pathway is crucial for the fatty acid uptake programme in activated CD4+ T cells. This pathway is required for full activation and rapid proliferation of naive and memory CD4+ T cells. PPARγ directly binds and induces genes associated with fatty acid uptake in CD4+ T cells in both mice and humans. The PPARγ-dependent fatty acid uptake programme is critical for metabolic reprogramming. Thus, we provide important mechanistic insights into the metabolic reprogramming mechanisms that govern the expression of key enzymes, fatty acid metabolism and the acquisition of an activated phenotype during CD4+ T cell activation.