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Tissue-resident memory T (T RM ) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of T RM cells are incompletely understood. Here we show that type 1 regulatory T (T reg ) cells, which express the transcription factor T-bet, promote the generation of CD8 + T RM cells. The absence of T-bet-expressing type 1 T reg cells reduces the presence of T RM cells in multiple tissues and increases pathogen burden upon infectious challenge. Using infection models, we show that type 1 T reg cells are specifically recruited to local inflammatory sites via the chemokine receptor CXCR3. Close proximity with effector CD8 + T cells and T reg cell expression of integrin-β8 endows the bioavailability of transforming growth factor-β in the microenvironment, thereby promoting the generation of CD8 + T RM cells. Tissue-resident memory T (T RM ) cells provide rapid front-line protection against infection. Veldhoen and colleagues demonstrate that the type 1 regulatory T cell subset supports generation of T RM cells.

Actin-binding proteins play a critical role in regulating the dynamic rearrangement of the actin cytoskeleton, which is essential for maintaining cellular homeostasis and facilitating various processes in eukaryotic cells. Cofilin-1 (Cfl1), an actin-binding protein, promotes the severing and depolymerization of actin filaments. To investigate the function of Cfl1 in mast cells, we generated Mcpt5-Cre-nf-Cfl1 fl/fl knock-in mice, expressing a non-functional form of Cfl1 (nf-Cfl1) instead of wildtype Cfl1 under the control of the connective tissue mast cell (CTMC)-specific promoter mast cell protease 5 (Mcpt5). Expression of nf-Cfl1 resulted in the complete absence of CTMCs. Notably, normal numbers of basophils were observed, in contrast to other mast cell-deficient mice. Interestingly, an inducible knock-in of nf-Cfl1 in mature mast cells did not affect the survival of mature mast cells. The Mcpt5-Cre-nf-Cfl1 fl/fl mice lacking CTMCs showed impaired induction of systemic anaphylaxis. However, they remained fully susceptible to 1-fluoro-2,4-dinitrobenzene-induced contact hypersensitivity and imiquimod-induced psoriasis-like dermatitis. In addition, clearance of vaccinia virus skin infection was unaltered. Thus, this study demonstrates that CTMCs are not essential in these inflammatory skin diseases. Deviating results in some other mast cell-deficient models suggest that the concomitant lack of basophils or residual CTMCs in these mouse models influence disease outcome. Taken together, the complete absence of CTMCs and the preserved presence of basophils in Mcpt5-Cre-nf-Cfl1 fl/fl mice establishes this model as a valuable tool for studying the specific role of CTMCs in different diseases.

Dendritic cells (DC) are specialized sentinel cells that bridge the innate and adaptive immune response and play a crucial role in shaping the adaptive immune response. Vitamin D, a known epidemiological risk factor for the development of several autoimmune diseases, influences the development of dendritic cells. Consequently, vitamin D metabolites are frequently used in protocols to develop therapeutic dendritic cell therapies for autoimmune diseases. However, the mechanisms by which vitamin D modulates DC function remain poorly understood. We investigated the effects of vitamin D on murine CD11c+ bone marrow derived DC (BMDC) function by analyzing global gene expression in CD11c+ BMDC generated in the presence (VitD-CD11c+BMDC) or absence (Veh-CD11c+BMDC) of the active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Seven genes were significantly increased in expression in both immature and LPS-matured VitD-CD11c+BMDC, one of which was CD31, a member of the immunoglobulin superfamily. Gene knockdown of CD31 enhanced the ability of VitD-CD11c+BMDC to prime naïve CD4+ T cells in vitro ; conversely, increased expression of CD31 on vehicle treated CD11c+BMDC restrained their T cell priming abilities. Time-lapse imaging of BMDC and CD4+ T cells during in vitro priming revealed that CD31 reduced the BMDC–T cell interaction time. Finally, we confirmed a similar effect of 1,25(OH)2D3 on human CD34+ cell-derived CD11c+DC, whereby DC generated in the presence of 1,25(OH)2D3 had increased CD31 expression. In summary, we show that both mouse and human DC generated in the presence of 1,25(OH)2D3 upregulate CD31 expression, resulting in a reduced ability to prime CD4+ T cells by impairing a stable cell-cell contact.

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare disease resulting from mutations in the gene encoding for the common β-chain of the β 2 -integrin family (CD18). The most prominent clinical symptoms are profound leukocytosis and high susceptibility to infections. Patients with LAD-1 are prone to develop autoimmune diseases, but the molecular and cellular mechanisms that result in coexisting immunodeficiency and autoimmunity are still unresolved. CD4 + FOXP3 + Treg are known for their essential role in preventing autoimmunity. To understand the role of Treg in LAD-1 development and manifestation of autoimmunity, we generated mice specifically lacking CD18 on Treg (CD18 Foxp3 ), resulting in defective LFA-1 expression. Here, we demonstrate a crucial role of LFA-1 on Treg to maintain immune homeostasis by modifying T cell–DC interactions and CD4 + T cell activation. Treg-specific CD18 deletion did not impair Treg migration into extralymphatic organs, but it resulted in shorter interactions of Treg with DC. In vivo, CD18 Foxp3 mice developed spontaneous hyperplasia in lymphatic organs and diffuse inflammation of the skin and in multiple internal organs. Thus, LFA-1 on Treg is required for the maintenance of immune homeostasis.

Actin-binding proteins play a critical role in regulating the dynamic rearrangement of the actin cytoskeleton, which is essential for maintaining cellular homeostasis and facilitating various processes in eukaryotic cells. Cofilin-1 (Cfl1), an actin-binding protein, promotes the severing and depolymerization of actin filaments. To investigate the function of Cfl1 in mast cells, we generated Mcpt5-Cre-nf-Cfl1 knock-in mice, expressing a non-functional form of Cfl1 (nf-Cfl1) instead of wildtype Cfl1 under the control of the connective tissue mast cell (CTMC)-specific promoter mast cell protease 5 (Mcpt5). Expression of nf-Cfl1 resulted in the complete absence of CTMCs. Notably, normal numbers of basophils were observed, in contrast to other mast cell-deficient mice. Interestingly, an inducible knock-in of nf-Cfl1 in mature mast cells did not affect the survival of mature mast cells. The Mcpt5-Cre-nf-Cfl1 mice lacking CTMCs showed impaired induction of systemic anaphylaxis. However, they remained fully susceptible to 1-fluoro-2,4-dinitrobenzene-induced contact hypersensitivity and imiquimod-induced psoriasis-like dermatitis. In addition, clearance of vaccinia virus skin infection was unaltered. Thus, this study demonstrates that CTMCs are not essential in these inflammatory skin diseases. Deviating results in some other mast cell-deficient models suggest that the concomitant lack of basophils or residual CTMCs in these mouse models influence disease outcome. Taken together, the complete absence of CTMCs and the preserved presence of basophils in Mcpt5-Cre-nf-Cfl1 mice establishes this model as a valuable tool for studying the specific role of CTMCs in different diseases.

Tissue-resident memory T (T ) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of T cells are incompletely understood. Here we show that type 1 regulatory T (T ) cells, which express the transcription factor T-bet, promote the generation of CD8 T cells. The absence of T-bet-expressing type 1 T cells reduces the presence of T cells in multiple tissues and increases pathogen burden upon infectious challenge. Using infection models, we show that type 1 T cells are specifically recruited to local inflammatory sites via the chemokine receptor CXCR3. Close proximity with effector CD8 T cells and T cell expression of integrin-β8 endows the bioavailability of transforming growth factor-β in the microenvironment, thereby promoting the generation of CD8 T cells.

Dendritic cells (DC) are specialized sentinel cells that bridge the innate and adaptive immune response and play a crucial role in shaping the adaptive immune response. Vitamin D, a known epidemiological risk factor for the development of several autoimmune diseases, influences the development of dendritic cells. Consequently, vitamin D metabolites are frequently used in protocols to develop therapeutic dendritic cell therapies for autoimmune diseases. However, the mechanisms by which vitamin D modulates DC function remain poorly understood. We investigated the effects of vitamin D on murine CD11c bone marrow derived DC (BMDC) function by analyzing global gene expression in CD11c BMDC generated in the presence (VitD-CD11c BMDC) or absence (Veh-CD11c BMDC) of the active vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25(OH) D ). Seven genes were significantly increased in expression in both immature and LPS-matured VitD-CD11c BMDC, one of which was CD31, a member of the immunoglobulin superfamily. Gene knockdown of CD31 enhanced the ability of VitD-CD11c BMDC to prime naïve CD4 T cells ; conversely, increased expression of CD31 on vehicle treated CD11c BMDC restrained their T cell priming abilities. Time-lapse imaging of BMDC and CD4 T cells during priming revealed that CD31 reduced the BMDC-T cell interaction time. Finally, we confirmed a similar effect of 1,25(OH) D on human CD34 cell-derived CD11c DC, whereby DC generated in the presence of 1,25(OH) D had increased CD31 expression. In summary, we show that both mouse and human DC generated in the presence of 1,25(OH) D upregulate CD31 expression, resulting in a reduced ability to prime CD4 T cells by impairing a stable cell-cell contact.