Th1 and Type 1 Cytotoxic T Cells Dominate Responses in T-bet Overexpression Transgenic Mice That Develop Contact Dermatitis

The cytokine milieu and dendritic cells (DCs) direct Th1 development. Yet, the control of Th1 polarization by T cell surface molecules remains ill-defined. We here report that CD47 expression on T cells serves as a self-control mechanism to negatively regulate type 1 cellular and humoral immune responses in vivo. Th2-prone BALB/c mice that lack CD47 (CD47−/−) displayed a Th1-biased Ab profile at steady state and after immunization with soluble Ag. CD47−/− mice mounted a T cell-mediated exacerbated and sustained contact hypersensitivity (CHS) response. After their adoptive transfer to naive CD47-deficient hosts 1 day before immunization with soluble Ag, CD47−/− as compared with CD47+/+CD4+ transgenic (Tg) T cells promoted the deviation of Ag-specific T cell responses toward Th1 that were characterized by a high IFN-γ:IL-4 cytokine ratio. Although selective CD47 deficiency on DCs led to increased IL-12p70 production, CD47−/−Tg T cells produced more IFN-γ and displayed higher T-bet expression than CD47+/+ Tg T cells in response to OVA-loaded CD47−/− DCs. CD47 as part of the host environment has no major contribution to the Th1 polarization responses. We thus identify the CD47 molecule as a T cell-negative regulator of type 1 responses that may limit unwanted collateral damage to maximize protection and minimize host injury.

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“…ϩ Th cells (38). Activated NK cells produce large amounts of IFN-␥, potentiate Th1 priming, and also participate in the CHS reaction (39,40).…”

Section: Discussionmentioning

confidence: 99%

CD47 Expression on T Cell Is a Self-Control Negative Regulator of Type 1 Immune Response

Bouguermouh

Van

Martel

et al. 2008

The Journal of Immunology

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“…T-bet expression in these mice is under the control of the human CD2 promoter, which allows it to be expressed exclusively in CD2-expressing cells. 10,11 In the present study, we further explored these mice, focusing in particular on the hematopoietic system, especially hematopoiesis of the mononuclear phagocyte lineage. Unexpectedly, we found that aged transgenic mice homozygous for the hCD2-T-bet tg allele spontaneously developed a pulmonary disease resembling human pulmonary alveolar proteinosis (PAP), a rare lung disorder characterized by the accumulation of surfactant protein within alveolar spaces due to functional defects in alveolar macrophages, and accompanied by local and bone marrow (BM) mononuclear phagocyte dysregulation.…”

Section: Naïve Cd4mentioning

confidence: 99%

“…11 We began by monitoring the viability of the littermates from hCD2-T-bet tg/wt (T-bet tg/wt ) mice. Of note, starting at ;20-weeks of age, more than 80% of the homozygous transgenic (T-bet tg/tg ) mice became moribund and died under For personal use only.…”

Section: T-betmentioning

confidence: 99%

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Iriguchi

Kikuchi

Kaneko

et al. 2015

Blood

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Key Points• Mice overexpressing T-bet in T cells show aberrant hematopoiesis of myeloid cells and functional conversion of regional macrophages.• The mice developed a severe PAP-like disease with a hematopoietic disorder resembling the human disease.Although overexpression of T-bet, a master transcription factor in type-1 helper T lymphocytes, has been reported in several hematologic and immune diseases, its role in their pathogenesis is not fully understood. In the present study, we used transgenic model mice (T-bet tg/wt and T-bet tg/tg ) to investigate the effects of T-bet overexpression selectively in T lymphocytes on the development of hematologic and immune diseases. The results showed that T-bet overexpression in T cells spontaneously induced maturation arrest in the mononuclear phagocyte lineage, as well as spontaneous dermatitis and pulmonary alveolar proteinosis (PAP)-like disease in T-bet tg/wt and T-bet tg/tg mice, respectively. T-bet tg/tg alveoli with the PAP phenotype showed remarkable reorganization of alveolar mononuclear phagocyte subpopulations and impaired function, in addition to augmented T-cell infiltration. In addition, PAP development in T-bet tg/tg mice was found to be associated with increased migration of myeloid cells from the bone marrow into the peripheral blood. These findings reveal an unexpected link between T-bet overexpression in T lymphocytes and the development of PAP caused by reorganization of mononuclear phagocytes in the lung, and provide new insight into the molecular pathogenesis of secondary PAP accompanied by hematologic disorders. (Blood. 2015;125(2):370-382)

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“…T-bet tg/tg mice were generated as previously described (14) and backcrossed to BALB/c mice for eight generations. T-bet 2/2 BALB/c mice were obtained from the The Jackson Laboratory (Bar Harbor, ME).…”

Section: Mice and Infectionmentioning

confidence: 99%

Role of Th1/Th17 Balance Regulated by T-bet in a Mouse Model of Mycobacterium avium Complex Disease

Matsuyama

Ishii

Yageta

et al. 2014

The Journal of Immunology

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Th1 immune responses are thought to be important in protection against intracellular pathogens. T-bet is a critical regulator for Th1 cell differentiation and Th1 cytokine production. The aim of this study was to determine the role of T-bet in host defense against Mycobacterium avium complex (MAC) infection. Wild-type mice, T-bet–deficient mice, and T-bet–overexpressing mice were infected with MAC via intratracheal inoculation. Macrophages and dendritic cells obtained from these mice were incubated with MAC. T-bet–deficient mice were highly susceptible to MAC, compared with wild-type mice and T-bet–overexpressing mice. Neutrophilic pulmonary inflammation was also enhanced in T-bet–deficient mice, but attenuated in T-bet–overexpressing mice, following MAC infection. Cytokine expression shifted toward Th1 in the lung and spleen of T-bet–overexpressing mice, but toward Th17 in T-bet–deficient mice. IFN-γ supplementation to T-bet–deficient mice reduced systemic MAC growth but did not reduce pulmonary inflammation. In contrast, neutralization of IL-17 in T-bet–deficient mice reduced pulmonary inflammation but did not affect mycobacterial growth in any organs tested. T-bet–deficient T cells tended to differentiate toward Th17 cells in vitro following exposure to MAC. Treatment with NO donor suppressed MAC-induced Th17 cell differentiation of T-bet–deficient T cells. This study identified that the fine balance between Th1 and Th17 responses is essential in defining the outcome of MAC disease. T-bet functions as a regulator for Th1/Th17 balance and is a critical determinant for host resistance to MAC infection by controlling cytokine and NO levels.

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Th1 and Type 1 Cytotoxic T Cells Dominate Responses in T-bet Overexpression Transgenic Mice That Develop Contact Dermatitis

Cited by 42 publications

References 37 publications

CD47 Expression on T Cell Is a Self-Control Negative Regulator of Type 1 Immune Response

CD47 Expression on T Cell Is a Self-Control Negative Regulator of Type 1 Immune Response

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

Role of Th1/Th17 Balance Regulated by T-bet in a Mouse Model of Mycobacterium avium Complex Disease

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