Daniel J. Campbell

The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation

Several subsets of Foxp3+ regulatory T cells (Treg cells) work in concert to maintain immune homeostasis. However, the molecular bases underlying the phenotypic and functional diversity of Treg cells remain obscure. We show that in response to interferon-γ, Foxp3+ Treg cells upregulated the T helper type 1 (TH1)-specifying transcription factor T-bet. T-bet promoted expression of the chemokine receptor CXCR3 on Treg cells, and T-bet+ Treg cells accumulated at sites of TH1 cell–mediated inflammation. Furthermore, T-bet expression was required for the homeostasis and function of Treg cells during type 1 inflammation. Thus, in a subset of CD4+ T cells, the activities of the transcription factors Foxp3 and T-bet are overlaid, which results in Treg cells with unique homeostatic and migratory properties optimized for the suppression of TH1 responses in vivo.

Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice

The cytokine thymic stromal lymphopoietin (TSLP) has been linked to human allergic inflammatory diseases. We show here that TSLP expression was increased in the lungs of mice with antigen-induced asthma, whereas TSLP receptor–deficient mice had considerably attenuated disease. Lung-specific expression of a Tslp transgene induced airway inflammation and hyperreactivity characterized by T helper type 2 cytokines and increased immunoglobulin E. The lungs of Tslp-transgenic mice showed massive infiltration of leukocytes, goblet cell hyperplasia and subepithelial fibrosis. TSLP was capable of activating bone marrow–derived dendritic cells to upregulate costimulatory molecules and produce the T helper type 2 cell–attracting chemokine CCL17. These findings suggest that TSLP is an important factor necessary and sufficient for the initiation of allergic airway inflammation.

Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin

The cytokine thymic stromal lymphopoietin (TSLP) has recently been implicated in the pathogenesis of atopic dermatitis (AD) and other allergic diseases in humans. To further characterize its role in this disease process, transgenic mice were generated that express a keratinocyte-specific, tetracycline-inducible TSLP transgene. Skin-specific overexpression of TSLP resulted in an AD-like phenotype, with the development of eczematous lesions containing inflammatory dermal cellular infiltrates, a dramatic increase in Th2 CD4+ T cells expressing cutaneous homing receptors, and elevated serum levels of IgE. These transgenic mice demonstrate that TSLP can initiate a cascade of allergic inflammation in the skin and provide a valuable animal model for future study of this common disease.

Rapid Acquisition of Tissue-specific Homing Phenotypes by CD4+ T Cells Activated in Cutaneous or Mucosal Lymphoid Tissues

Effector and memory T cells can be subdivided based on their ability to traffic through peripheral tissues such as inflamed skin and intestinal lamina propria, a property controlled by expression of ‘tissue-specific’ adhesion and chemoattractant receptors. However, little is known about the development of these selectively homing T cell subsets, and it is unclear whether activation in cutaneous versus intestinal lymphoid organs directly results in effector/memory T cells that differentially express adhesion and chemoattracant receptors targeting them to the corresponding nonlymphoid site. We define two murine CD4+ effector/memory T cell subsets that preferentially localize in cutaneous or intestinal lymphoid organs by their reciprocal expression of the adhesion molecules P-selectin ligand (P-lig) and α4β7, respectively. We show that within 2 d of systemic immunization CD4+ T cells activated in cutaneous lymph nodes upregulate P-lig, and downregulate α4β7, while those responding to antigen in intestinal lymph nodes selectively express high levels of α4β7 and acquire responsiveness to the intestinal chemokine thymus-expressed chemokine (TECK). Thus, during an immune response, local microenvironments within cutaneous and intestinal secondary lymphoid organs differentially direct T cell expression of these adhesion and chemoattractant receptors, targeting the resulting effector T cells to the inflamed skin or intestinal lamina propria.

Compartmentalized Control of Skin Immunity by Resident Commensals

Skin Specifics Much of the recent attention paid to the trillions of bacteria that colonize our bodies has been given to the bacteria that reside in the gut. Naik et al. (p. 1115, published online 26 July) report that colonization of the skin with commensal bacteria is important for tuning effector T cell responses in the skin and for protective immunity against cutaneous infection with the parasite Leishmania major in mice. In contrast, selective depletion of the gut microbiota, which plays an important role in modulating immune responses in the gut, had no impact on T cell responses in the skin. The skin microbiota play a selective role in modulating immunity in the skin of mice. Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease.

Chemokines in the systemic organization of immunity

Summary:  Directed cellular migrations underlie immune system organization. Chemokines and their receptors (along with surface‐adhesion molecules) are central to these migrations, targeting developing and mature leukocytes to tissues and microenvironments suitable for their differentiation and function. The chemokine CXCL12 and its receptor CXCR4 play a central role in the migration of hematopoietic stem cells, and several chemokine receptors are transiently expressed during distinct stages of B‐ and T‐cell development. In the periphery, mature naïve B and T cells utilize the receptors CCR7, CXCR4, and CXCR5 to recirculate through specialized microenvironments within the secondary lymphoid tissues, while effector and memory lymphocytes express bewildering patterns of adhesion molecules and chemokine receptors that allow them to function within microenvironments and non‐lymphoid tissues inaccessible to naïve cells. Here, we summarize the role of chemokines and their receptors in the spatial organization of the immune system and consider the implications for immune function.

Altering the distribution of Foxp3+ regulatory T cells results in tissue-specific inflammatory disease

CD4+Foxp3+ regulatory T cells (T reg) are essential for maintaining self-tolerance, but their functional mechanisms and sites of action in vivo are poorly defined. We examined the homing receptor expression and tissue distribution of T reg cells in the steady state and determined whether altering their distribution by removal of a single chemokine receptor impairs their ability to maintain tissue-specific peripheral tolerance. We found that T reg cells are distributed throughout all nonlymphoid tissues tested, and are particularly prevalent in the skin, where they express a unique CCR4+CD103hi phenotype. T reg cell expression of CCR4 and CD103 is induced by antigen-driven activation within subcutaneous lymph nodes, and accumulation of T reg cells in the skin and lung airways is impaired in the absence of CCR4 expression. Mice with a complete loss of CCR4 in the T reg cell compartment develop lymphocytic infiltration and severe inflammatory disease in the skin and lungs, accompanied by peripheral lymphadenopathy and increased differentiation of skin-tropic CD4+Foxp3+ T cells. Thus, selectively altering T reg cell distribution in vivo leads to the development of tissue-specific inflammatory disease.

Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells.

FOXP3+ regulatory T (Treg) cells are a broadly acting and potent anti-inflammatory population of CD4+ T cells essential for maintaining immune homeostasis and preventing debilitating autoimmunity. Based on chemokine receptor expression, we identified distinct populations of Treg cells in human blood expected to colocalize with different Th cell subsets. Although each population was functionally suppressive, they displayed unique patterns of pro- and anti-inflammatory cytokine production, differentially expressed lineage-specifying transcription factors, and responded differently to antigens associated with Th1 and Th17 responses. These results highlight a previously unappreciated degree of phenotypic and functional diversity in human Treg cells that allows subsets with unique specificities and immunomodulatory functions to be targeted to defined immune environments during different types of inflammatory responses.

Chemokines in Lymphocyte Trafficking and Intestinal Immunity

Lymphocyte migration through gut‐associated lymphoid tissues (GALT) and into intestinal effector sites is critical to intestinal immune system function and homeostasis. Chemokines contribute to lymphocyte trafficking by triggering integrin activation and firm arrest in the vasculature and mediating chemotactic localization within tissues. Several chemokines have been identified that are expressed in the GALT and/or the intestines themselves (TECK/CCL25, MEC/CCL28, and MIP‐3α/CCL20) and play a role in intestinal lymphocyte localization, including unification of intestinal and other mucosa‐associated effector sites; segmental specialization of the intestines; and subset selective localization to the intestines. This review examines the role of these chemokines (and their receptors CCR9, CCR10, and CCR6, respectively) in lymphocyte homing to the GALT, in the induction and differentiation of intestinal effector and memory lymphocytes, and in the homeostatic and inflammatory localization of lymphocytes to the intestines.

Foxp3+ regulatory T cells maintain immune homeostasis in the skin

Cutaneous immune responses must be tightly controlled to prevent unwanted inflammation in response to innocuous antigens, while maintaining the ability to combat skin-tropic pathogens. Foxp3+ regulatory T (T reg) cells are potent immune regulators and are found at high frequency in both human and mouse skin. Although T reg cells migrate to the skin and can dampen immune responses during experimentally induced inflammation or infection, the importance of cutaneous T reg cells for maintaining normal immune homeostasis in the skin has not been addressed. To selectively block T reg cell function in the skin, we restored the T reg cell compartment in Foxp3-deficient scurfy mice with cells whose ability to migrate to the skin was impaired because of targeted mutation of α-1,3-fucosyltransferase VII (Fut7). Although Fut7-deficient T reg cells were present at normal frequency and could function in all other tissues examined, these animals rapidly developed severe cutaneous inflammation. Thus, skin-resident T reg cell are essential for maintaining normal immune homeostasis at this site.