Most of the immunoglobulin A (IgA) in the gut is generated by B cells in the germinal centers of Peyer's patches through a process that requires the presence of CD4+ follicular B helper T(TFH) cells. The nature of these TFH cells in Peyer's patches has been elusive. Here, we demonstrate that suppressive Foxp3+CD4+ T cells can differentiate into TFH cells in mouse Peyer's patches. The conversion of Foxp3+ T cells into TFH cells requires the loss of Foxp3 expression and subsequent interaction with B cells. Thus, environmental cues present in gut Peyer's patches promote the selective differentiation of distinct helper T cell subsets, such as TFH cells.

Acute diarrheal illness is a global health problem that may be exacerbated by concurrent infection. Using Citrobacter rodentium, a murine model of attaching and effacing diarrheagenic Escherichia coli, we demonstrate that persistent Helicobacter hepaticus infection modulates host responses to diarrheal disease, resulting in delayed recovery from weight loss and from tissue damage. Chronic colitis in concurrently infected mice is characterized by macrophage and Foxp3+ regulatory T-cell accumulation. Prolonged disease is also associated with increased interleukin-17 expression, which may be due to suppression of gamma interferon during the acute phase of diarrheal infection. This new model of polymicrobial infection provides insight into the mechanism by which subclinical infection can exacerbate morbidity due to an unrelated self-limiting infection.

The intestinal tract is in intimate contact with the commensal microflora. Nevertheless, how commensals communicate with cells to ensure immune homeostasis is still unclear. In this study, we found that gut flora DNA (gfDNA) plays a major role in intestinal homeostasis through Toll-like receptor 9 (TLR9) engagement. Tlr9−/− mice displayed increased frequencies of CD4+Foxp3+ regulatory T (Treg) cells within intestinal effector sites and reduced constitutive IL-17- and IFN-γ-producing effector T (Teff) cells. Complementing this, gfDNA limited lamina propria dendritic cell-induced Treg cell conversion in vitro. Further, Treg/Teff cell disequilibrium in Tlr9−/− mice led to impaired immune responses to oral infection and to oral vaccination. Impaired intestinal immune responses were recapitulated in mice treated with antibiotics and were reversible after reconstitution with gfDNA. Together, these data point to gfDNA as a natural adjuvant for priming intestinal responses via modulation of Treg/Teff cell equilibrium.

The vertebrate immune system has important self-check mechanisms that prevent it from destroying the host's own tissues. Regulatory T cells are part of this suppressive control, and on page 271 in this issue, Wing et al. (1) define the role of cytotoxic T lymphocyte antigen 4 (CTLA-4)--a protein that is preferentially expressed by regulatory T cells--in restraining the immune response when needed and in maintaining self tolerance. Therapies based on CTLA-4 are currently used, or in clinical trials, for treating autoimmune conditions such as rheumatoid arthritis or to augment immune responses directed at tumors, respectively, so understanding the specific role of CTLA-4 in regulatory T cell function may further improve and expand such clinical approaches. Optimal T cell proliferation and acquisition of effector functions require intracellular signals elicited by both the T cell receptor and by a co-receptor, CD28 (2). Although CTLA-4 binds to the same ligands as CD28 (with much higher affinity), it restricts T cell activation. CD28 and CTLA-4 also differ in their expression on different subsets of T cells. CD28 is expressed on most CD4+ T cells and almost all CD8+ T cells. CTLA-4 expression is induced in all T cells transiently after T cell receptor activation. However, among non-activated (resting) CD4+ T cells, CTLA-4 is constitutively expressed on regulatory T cells that express the forkhead transcription factor, Foxp3 (3). To clearly define a role for CTLA-4 in regulatory T cell function, Wing et al. deleted expression of the protein in mice, specifically in regulatory T cells that express Foxp3. These animals appeared to be normal until 7 weeks of age, when they rapidly developed systemic autoimmunity. Thus, CTLA-4 deficiency in regulatory T cells alone is sufficient to cause fatal disease, and maintenance of its expression in activated effector T cells is insufficient to prevent this outcome. Previous studies suggested that CTLA-4 might be involved in mediating the suppressor function of Foxp3-expressing regulatory T cells both in vivo (4, 5) and in vitro (6, 7). But interpretation of these studies is problematic, as they used treatment with an antibody to CTLA-4, or regulatory T cells from mice with a global deficiency of CTLA-4. Anti-CTLA-4 may have abrogated suppression by indirectly activating effector T cells. Although mice lacking CTLA-4 do have Foxp3-expressing regulatory T cells, isolating them from these animals has required immunologic manipulations that may have influenced regulatory T cell development (5, 7). These problems are absent in the analysis of regulatory T cells from the mice of Wing et al. that have a selective loss of CTLA-4. Selective CLTA-4 deficiency did not appear to alter the development or homeostasis of regulatory T cells, nor render them pathogenic. These cells also remained anergic but were less suppressive in vitro than their wild-type counterparts. Most notably, regulatory T cells from these mice were less suppressive in vivo, as immunodeficient mice reconstituted with total CD4+ T cells from these mice had enhanced immune responses to transplanted tumors.