Tolerogenic insulin peptide therapy precipitates type 1 diabetes.

Daniel et al. (https://doi.org/10.1084/jem.20110574) have previously published in JEM a study on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes. Our study now challenges these results and shows that osmotic pump delivery of the modified insulin peptide R22E did not prevent hyperglycemia, accelerated disease onset, increased its incidence, and worsened insulitis.

Old dogs and new tricks: defective peripheral regulatory T cell generation in aged mice.

Tolerance is a developmentally acquired property of the vertebrate immune system, in part ensured by regulatory CD4⁺ lymphocytes (Treg cells) expressing the Foxp3 transcription factor. Recent work has shown that thymic emigrants are the preferential source of peripherally generated Treg cells. A new report in this issue of the European Journal of Immunology [Eur. J. Immunol. 2013. 43: 2598-2604] describes a cell autonomous defect in Foxp3 induction in aged CD4⁺ cells in mice. Immune homeostasis becomes progressively less robust as ontogeny gives way to aging, and a key feature of senescence is thymic involution and the impaired T-cell turnover that follows. In this Commentary, we discuss the implications of these recent findings for our understanding of the induction of tolerance to peripheral antigens in aging.

Marginal zone B cells in lymphocyte activation and regulation.

Marginal zone (MZ) B cells, together with other strategically located innate cells, constitute the first line of defense against blood-borne microorganisms, viruses and toxins in the spleen. Their fast and efficient protective antibody responses are well characterized; however, much less is known of their interactions with other cell types during immune responses. Recent work has demonstrated that MZ B cells can directly activate T cells; and MZ B cells also interact with other antigen presenting cells, transporting and concentrating antigen during the course of T-dependent and T-independent immune responses.

Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion.

Expression of the IL-2 receptor alpha chain (CD25) by peripheral CD4 T cells follows cellular activation. However, CD25 expression by CD4 cells is widely used as a marker to identify regulatory T cells (T(R)), although cells with regulatory properties are also found in the CD4+CD25- subset. By using in vivo functional assays and Foxp3 expression as a faithful marker of T(R) differentiation, we have evaluated the requirements for CD25 expression by peripheral T(R). We first show that in vivo depletion of CD25+ cells prevents the development of spontaneous encephalomyelitis in recombination-activating gene (RAG)-deficient anti-myelin basic protein T cell antigen receptor (TCR) transgenic mice, and allows disease induction in otherwise healthy RAG-competent transgenic mice. Similar treatment in normal thymectomized animals is followed by the fast recovery of a normal number of CD25+ T(R). Consistently, Foxp3-expressing T(R) encompassed in the CD25- cell population convert to CD25+ after homeostatic expansion and are selectable by IL-2 in vitro. Surface expression of CD25 on T(R) is controlled by the activity of conventional CD4 cells and is fully labile because it can be lost and regained without affecting the functional potential of the cells. These findings reveal that Foxp3-expressing CD25- cells constitute a peripheral reservoir of differentiated T(R), recruited to the CD25+ pool upon homeostatic expansion and/or activation. This analysis, together with the notion that physiological commitment of T(R) takes place exclusively in the thymus should help for the interpretation of experiments assessing peripheral T(R) differentiation from naive CD4 T cells, defined as CD25-.

Marginal zone B cell physiology and disease.

Mature B lymphocytes do not constitute a homogenous pool of cells, and it is now clear that several functionally and developmentally distinct subsets exist. Of these, marginal zone (MZ) B cells are a subset of peripheral B cells that respond vigorously to blood-borne infections, and play a vital role, particularly in host survival of infection by encapsulated bacteria. Their fast activation and differentiation to antibody-secreting plasma cells allows MZ B cells to bridge the gap between innate and adaptive immunity, effected mainly by the more prolific follicular B cells. Like other naturally activated lymphocytes, MZ B cells may also play a role in homeostasis and tolerance, apart from combating infection. Here we will review some of the extracellular signals that affect their development, selection and function. We conclude by examining how their repertoire, location and interactions with other cell types may be important in the induction of autoimmune disease.

Development and selection of marginal zone B cells.

It is now clear that functionally distinct subsets of mature peripheral B cells exist. Of these subsets, marginal zone (MZ) B cells in the spleen are strategically positioned at the blood-lymphoid interface and are programmed to initiate a fast and intense antibody response to blood-borne viral and bacterial agents. Their ability to respond vigorously to antigen and polyclonal activators make MZ B cells key players in the early response to pathogens in the bloodstream. The specialized functions of these innate-like lymphocytes bridge the gap between the early innate immune response and the slower adaptive antibody response, affected mainly by the more prolific follicular B cells. MZ B cells, like B1 cells, are important not only to combat infections but also in the maintenance of host homeostasis. Here we discuss some aspects of MZ B-cell selection and function in health and disease.

Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide.

Regulatory CD4 T cells (Treg) control inflammatory reactions to commensal bacteria and opportunist pathogens. Activation of Treg functions during these processes might be mediated by host-derived proinflammatory molecules or directly by bacterial products. We tested the hypothesis that engagement of germline-encoded receptors expressed by Treg participate in the triggering of their function. We report that the subset of CD4 cells known to exert regulatory functions in vivo (CD45RB(low) CD25(+)) selectively express Toll-like receptors (TLR)-4, -5, -7, and -8. Exposure of CD4(+) CD25(+) cells to the TLR-4 ligand lipopolysaccharide (LPS) induces up-regulation of several activation markers and enhances their survival/proliferation. This proliferative response does not require antigen-presenting cells and is augmented by T cell receptor triggering and interleukin 2 stimulation. Most importantly, LPS treatment increases CD4(+) CD25(+) cell suppressor efficiency by 10-fold and reveals suppressive activity in the CD4(+) CD45RB(low) CD25(-) subset that when tested ex-vivo, scores negative. Moreover, LPS-activated Treg efficiently control naive CD4 T cell-dependent wasting disease. These findings provide the first evidence that Treg respond directly to proinflammatory bacterial products, a mechanism that likely contributes to the control of inflammatory responses.