Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris

Mechanisms of tolerance break against desmoglein 3 (Dsg3) in patients with pemphigus vulgaris (PV) producing pathogenic anti-Dsg3 IgG autoantibodies are unclear. In this study, using a novel PV mouse model involving Dsg3 knockout mice, we investigated the mechanisms leading to production of autoantibodies against Dsg3. Adoptive transfer of Dsg3(-/-) splenocytes immunized with recombinant mouse Dsg3 to Rag2(-/-) recipient mice expressing Dsg3 resulted in the stable production of anti-Dsg3 IgG and development of PV phenotypes including oral erosions with suprabasilar acantholysis. When purified T and B cells from Dsg3(-/-), Dsg3(+/-) or Dsg3(+/+) mice were mixed with various combinations and transferred to Rag2(-/-) mice, pathogenic anti-Dsg3 IgG production was observed only with a combination of Dsg3(-/-) T and Dsg3(-/-) B cells but not with the other combinations. These results suggest that loss of tolerance against Dsg3 in both B and T cells is important for the development of autoimmune state of PV.     

Diversification and senescence of Foxp3+ regulatory T cells during experimental autoimmune encephalomyelitis

The fate of Foxp3⁺ regulatory T (Treg) cells responding during autoimmunity is not well defined. We observed a marked elevation in KLRG1⁺ (where KLRG1 stands for killer cell lectin‐like receptor G1) CNS‐infiltrating Treg cells in experimental autoimmune encephalomyelitis (EAE), and assessed their origin and properties. KLRG1⁺ Treg cells showed increased activation marker expression, Foxp3 and CD25 levels, and more rapid cell cycling than KLRG1^? cells. KLRG1^? Treg cells converted into KLRG1⁺ cells and this was increased in autoimmune inflammation. Conversion was unidirectional; KLRG1⁺ Treg cells did not revert to a KLRG1^? state. KLRG1⁺ but notKLRG1^?Treg cells survived poorly, indicative of terminal differentiation. This was associated with diminished BCL2 and increased apoptosis of isolated cells. KLRG1 was also upregulated on iTreg cells after transfer and EAE induction or on iTreg cells developing spontaneously during EAE. KLRG1⁺ Treg cells produced more IL‐10 and had altered effector cytokine production compared with their KLRG1^? counterparts. Despite their differences, KLRG1⁺ and KLRG1^? Treg cells proved similarly potent in suppressing EAE. KLRG1⁺ and KLRG1^? populations were phenotypically heterogeneous, with the extent and pattern of activation marker expression dependent both on cellular location and inflammation. Our results support an extensive diversification of Treg cells during EAE, and associate KLRG1 with altered Treg‐cell function and senescence.     

Foxp3+ regulatory T cells promote lung epithelial proliferation

Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality each year. There is a paucity of information regarding the mechanisms necessary for ARDS resolution. Foxp3⁺ regulatory T cells (Foxp3⁺ T_reg cells) have been shown to be an important determinant of resolution in an experimental model of lung injury. We demonstrate that intratracheal delivery of endotoxin (lipopolysaccharide) elicits alveolar epithelial damage from which the epithelium undergoes proliferation and repair. Epithelial proliferation coincided with an increase in Foxp3⁺ T_reg cells in the lung during the course of resolution. To dissect the role that Foxp3⁺ T_reg cells exert on epithelial proliferation, we depleted Foxp3⁺ T_reg cells, which led to decreased alveolar epithelial proliferation and delayed lung injury recovery. Furthermore, antibody-mediated blockade of CD103, an integrin, which binds to epithelial expressed E-cadherin decreased Foxp3⁺ T_reg numbers and decreased rates of epithelial proliferation after injury. In a non-inflammatory model of regenerative alveologenesis, left lung pneumonectomy, we found that Foxp3⁺ T_reg cells enhanced epithelial proliferation. Moreover, Foxp3⁺ T_reg cells co-cultured with primary type II alveolar cells (AT2) directly increased AT2 cell proliferation in a CD103-dependent manner. These studies provide evidence of a new and integral role for Foxp3⁺ T_reg cells in repair of the lung epithelium.     

Foxp3+ regulatory T cells: selfishness under scrutiny

The Foxp3+ T cell lineage is thought to arise from self-specific precursors during development. By using a unique mouse model, Pacholczyk et al. (2007) present compelling evidence that self-specific cells are exceedingly rare among Foxp3(-) and, surprisingly, Foxp3+ subsets.     

FTY720-induced conversion of conventional Foxp3- CD4+ T cells to Foxp3+ regulatory T cells in NOD mice

Citation Sun Y, Wang W, Shan B, Di J, Chen L, Ren L, Li W, Li D‐J, Lin Y. FTY720‐induced conversion of conventional Foxp3^?CD4⁺ T cells to Foxp3⁺ regulatory T cells in NOD mice. Am J Reprod Immunol 2011; 66: 349–362 Problem FTY720 is known as an agonist of sphingosine‐1‐phosphate (S1P) receptor, but little is known about the possibility that FTY720 induces the conversion of conventional Foxp3^?CD4⁺ T cells to Foxp3⁺ regulatory T cells in non‐obese diabetic (NOD) mice. Method of study FTY720 treatment was performed using Foxp3^?CD4⁺ T cells purified from NOD mice. Results FTY720 caused an increase in Foxp3⁺ Treg cells in lymphoid organs in NOD mice. FTY720 effectively induced Foxp3 expression in Foxp3^?CD4⁺ T cells both in vitro and in vivo, an effect that was inhibited by a TGF‐β‐neutralizing antibody or the proinflammatory cytokine IL‐6. T‐cell‐mediated embryo rejection in NOD mice was prevented upon FTY720 treatment. Conclusions The use of FTY720 along with Ag administration may represent a useful therapeutic strategy to selectively expand Ag‐specific Foxp3⁺ Tregs to intervene autoimmune and infectious diseases.     

Nonself-antigens are the cognate specificities of Foxp3+ regulatory T cells

The majority of regulatory Foxp3+CD4+ T cells naturally arises in the thymus. It has been proposed that T cell receptors (TCRs) on these cells recognize self-MHC class II-peptide complexes with high or higher affinity and that their specificities mirror specificities of autoreactive T cells. Here, we analyzed hundreds of TCRs derived from regulatory or nonregulatory T cells and found little evidence that the former population preferably recognizes self-antigens as agonists. Instead, these cells recognized foreign MHC-peptide complexes as often as nonregulatory T cells. Our results show that high-affinity, autoreactive TCRs are rare on all CD4+ T cells and suggest that selecting self-peptide is different from the peptide that activates the same regulatory T cells in the periphery.     

Oestrogen-mediated protection of experimental autoimmune encephalomyelitis in the absence of Foxp3+ regulatory T cells implicates compensatory pathways including regulatory B cells

Oestrogen (17β‐oestradiol, E₂) is a highly effective treatment for experimental autoimmune encephalomyelitis (EAE) that may potentiate Foxp3⁺ regulatory T (Treg) cells, which in turn limit the expansion of encephalitogenic T‐cell specificities. To determine if Treg cells constitute the major non‐redundant protective pathway for E₂, we evaluated E₂ protection of EAE after targeted deletion of Foxp3 expression in Foxp3‐DTR mice. Unexpectedly, E₂‐treated Foxp3‐deficient mice were completely protected against clinical and histological myelin oligodendrocyte glycoprotein (MOG)‐35‐55 peptide‐induced EAE before succumbing to diphtheria toxin‐induced mortality. This finding indicated the presence of alternative E₂‐dependent EAE‐protective pathways that could compensate for the lack of Treg cells. Further investigation revealed that E₂ treatment inhibited proliferation and expression of CCL2 and CXCL2, but enhanced secretion of interleukin‐10 (IL‐10) and IL‐13 by MOG‐35‐55‐specific spleen cells. These changes occurred concomitantly with increased expression of several chemokines and receptors, including CXCL13 and CXCR5, and the negative co‐activation molecules, PD‐L1 and B7.2, by B cells and dendritic cells. Furthermore, E₂ treatment resulted in higher percentages of spleen and lymph node T cells expressing IL‐17, interferon‐γ and tumour necrosis factor‐α, but with lower expression of CCR6, suggesting sequestration of MOG‐35‐55 peptide‐specific T cells in peripheral immune organs. Taken together, these data suggest that E₂‐induced mechanisms that provide protection against EAE in the absence of Foxp3⁺ Treg cells include induction of regulatory B cells and peripheral sequestration of encephalitogenic T cells.     

Role of activin A in the induction of Foxp3+ and Foxp3- CD4+ regulatory T cells

Regulatory T cells (Tregs) play a crucial role in the maintenance of immune homeostasis. The two best studied types of CD4(+) regulatory T cells are the Foxp3(+) Tregs and the T regulatory type 1 (Tr1) cells. CD4(+) regulatory T cells play a protective role in autoimmune disease. On the other hand, they also may have pathogenic properties in infectious diseases and carcinogenesis. Because of their potential for the therapy of various human diseases, factors responsible for expanding regulatory T cells are of interest. One of these factors, the TGFbeta family member activin A, is expressed in different inflammatory conditions, such as inflammatory bowel disease, rheumatoid arthritis, and asthma. Although activin A might have pro- and anti-inflammatory properties depending on the context of expression, this review focuses on the role of activin A for the expansion of the CD4(+) regulatory T-cell pool.     

CD8+ Foxp3+ T cells share developmental and phenotypic features with classical CD4+ Foxp3+ regulatory T cells but lack potent suppressive activity

"Suppressor T cells" were historically defined within the CD8(+) T-cell compartment and recent studies have highlighted several naturally occurring CD8(+) Foxp3(-) Treg populations. However, the relevance of CD8(+) Foxp3(+) T cells, which represent a minor population in both thymi and secondary lymphoid organs of nonmanipulated mice, remains unclear. We here demonstrate that de novo Foxp3 induction in peripheral CD8(+) Foxp3(-) T cells is counter-regulated by DC-mediated co-stimulation via CD80/CD86. CD8(+) Foxp3(+) T cells fail to develop in TCR-transgenic mice with Rag1(-/-) background, similar to classical CD4(+) Foxp3(+) Tregs. Notably, both naturally occurring and induced CD8(+) Foxp3(+) T cells express bona fide Treg markers including CD25, GITR, CTLA4 and CD103, and show defective IFN-γ production upon restimulation when compared with their CD8(+) Foxp3(-) counterparts. However, utilizing DEREG transgenic mice for the isolation of Foxp3(+) cells by eGFP reporter expression, we demonstrate that induced CD8(+) Foxp3(+) T cells similar to activated CD8(+) Foxp3(-) T cells only mildly suppress T-cell proliferation and IFN-γ production. We therefore categorize CD8(+) Foxp3(+) T cells as a tightly controlled population sharing certain developmental and phenotypic properties with classical CD4(+) Foxp3(+) Tregs, but lacking potent suppressive activity.