TIMs: central regulators of immune responses

Exhaustion of T cell responses during chronic viral infections has been observed in both mouse and man and has been attributed to up-regulation of PD-1 on the surface of exhausted T cells. In patients with chronic human HIV infection, T cell exhaustion leads to opportunistic infections associated with AIDS. However, not all the exhausted T cells express PD-1, suggesting that other molecules may be involved in the phenotype. A new study now demonstrates a central role for T cell immunoglobulin and mucin domain–containing protein-3 (TIM-3) in T cell exhaustion during chronic HIV infection and suggests that TIM-3 may be a novel therapeutic target in chronic viral diseases

IL-12– and IL-23–induced T helper cell subsets: birds of the same feather flock together

Traditionally, CD4+ T cells have been separated into two different subsets named T helper (Th)1 and Th2. A new IL-23–driven subset of Th cells called ThIL-17 has now been described. The data suggest that IL-23 plays an important role in the differentiation of autoreactive pathogenic T cells. Whether these IL-23–induced ThIL-17 cells are a unique subset or are related to other Th subsets is discussed

The paradox of being a woman teacher

In this article I follow genealogical lines of analysis in an attempt to map the different discourses and practices that interweave women’s position in education today. I have theorised education as a nexus of created paradoxical spaces, where the female self has attempted to surpass closed boundaries and to question the dichotomy of the feminised private and/or the masculine public. I have also considered the importance of time restrictions upon women’s lives and have paid attention to the multifarious ways these lives are highly structured by specific space/time regulations. The genealogical cartography I have drawn, depicts various positions, where the female self has created parodic unities and temporary coalitions. Finally in tracing exit points that education has offered women, I have considered some of the implications of feminist theories for the subversion of the various dilemmas and dichotomies the female subject has lived through

CD4+CD25−Foxp3− Th1 cells are the source of IL-10–mediated immune suppression in chronic cutaneous leishmaniasis

Nonhealing forms of leishmaniasis in humans are commonly associated with elevated levels of the deactivating cytokine IL-10, and in the mouse, normally chronic infections can be cleared in the absence of IL-10. Using a Leishmania major strain that produces nonhealing dermal lesions in a T helper type 1 (Th1) cell–polarized setting, we have analyzed the cellular sources of IL-10 and their relative contribution to immune suppression. IL-10 was produced by innate cells, as well as CD4+CD25+Foxp3+ and CD4+CD25−Foxp3− T cells in the chronic lesion. Nonetheless, only IL-10 production by antigen-specific CD4+CD25−Foxp3− T cells, the majority of which also produced IFN-γ, was necessary for suppression of acquired immunity in Rag−/− reconstituted mice. Surprisingly, Rag−/− mice reconstituted with naive CD4+ T cells depleted of natural T regulatory cells developed more severe infections, associated with elevated levels of IL-10 and, especially, Th2 cytokines in the site. The data demonstrate that IL-10–producing Th1 cells, activated early in a strong inflammatory setting as a mechanism of feedback control, are the principal mediators of T cell–derived IL-10–dependent immune suppression in a chronic intracellular infection

Autopathogenic T Helper Cell Type 1 (Th1) and Protective Th2 Clones Differ in Their Recognition of the Autoantigenic Peptide of Myelin Proteolipid Protein

We previously generated a panel of T helper cell 1 (Th1) clones specific for an encephalitogenic peptide of myelin proteolipid protein (PLP) peptide 139–151 (HSLGKWLGHPDKF) that induces experimental autoimmune encephalomyelitis (EAE) upon adoptive transfer. In spite of the differences in their T cell receptor (TCR) gene usage, all these Th1 clones required W144 as the primary and most critical TCR contact residue for the activation. In this study, we determined the TCR contact residues of a panel of Th2/Th0 clones specific for the PLP peptide 139–151 generated either by immunization with the PLP 139–151 peptide with anti– B7-1 antibody or by immunization with an altered peptide Q144. Using alanine-substituted peptide analogues of the native PLP peptide, we show that the Th2 clones have shifted their primary contact residue to the NH2-terminal end of the peptide. These Th2 cells do not show any dependence on the W144, but show a critical requirement for L141/G142 as their major TCR contact residue. Thus, in contrast with the Th1 clones that did not proliferate to A144-substituted peptide, the Th2 clones tolerated a substitution at position 144 and proliferated to A144 peptide. This alternative A144 reactive repertoire appears to have a critical role in the regulation of autoimmune response to PLP 139–151 because preimmunization with A144 to expand the L141/G142-reactive repertoire protects mice from developing EAE induced with the native PLP 139–151 peptide. These data suggest that a balance between two different T cell repertoires specific for same autoantigenic epitope can determine disease phenotype, i.e., resistance or susceptibility to an autoimmune disease

A chimeric T cell receptor with super‐signaling properties

A key question yet to be resolved concerns the structure and function relationship of the TCR complex. How does antigen recognition by the TCR‐αβ chains result in the activation of distinct signal transduction pathways by the CD3‐γδϵ/ζ complex? To investigate which part of the TCR‐β chain is involved in TCR signaling, we exchanged different domains of the constant regions of the TCR‐β chain with the corresponding TCR‐γ chain domains. We show here that hybridoma cells expressing a chimeric TCR‐β chain (βIII) containing intracellular and transmembrane TCR‐γ amino acids, together with a wild‐type TCR‐α (αwt) chain, were 10 times more sensitive to antigenic stimulation compared to cells expressing TCR‐αwt/βwt chains. This super‐signaling phenotype of the βIII chain was observed in two different TCRs. One specific for an alloantigen (I‐Abm12) and one for an autoantigen (I‐Ab/MOG35-55). We found that this chimeric αwt/βIII TCR had normal association with CD3‐γδϵ and ζ chains. To investigate the effect of the chimeric βIII chain in transgenic T cells, we made MOG35-55‐specific TCR transgenic mice expressing either the αwt/βwt or chimeric αwt/βIII TCR. Similar to what was observed in hybridoma cells, transgenic αwt/βIII T cells showed a super‐signaling phenotype upon antigenic stimulation. Further studies may help us understand the effect of increased TCR signaling on autoimmunity and may lead to the identification of signaling molecules that can be targeted to stop the progression of autoimmune disorders such as multiple sclerosi

Reduced Self-Reactivity of an Autoreactive T Cell After Activation with Cross-reactive Non–Self-Ligand

Autoreactive CD4+ T lymphocytes are critical to the induction of autoimmune disease, but because of the degenerate nature of T cell receptor (TCR) activation such receptors also respond to other ligands. Interaction of autoreactive T cells with other non–self-ligands has been shown to activate and expand self-reactive cells and induce autoimmunity. To understand the effect on the autoreactivity of naive cross-reactive T cells of activation with a potent nonself ligand, we have generated a TCR transgenic mouse which expresses a TCR with a broad cross-reactivity to a number of ligands including self-antigen. The activation of naive transgenic recombination activating gene (Rag)2−/− T cells with a potent non–self-ligand did not result in a enhancement of reactivity to self, but made these T cells nonresponsive to the self-ligand and anti-CD3, although they retained a degree of responsiveness to the non–self-ligand. These desensitized cells had many characteristics of anergic T cells. Interleukin (IL)-2 production was selectively reduced compared with interferon (IFN)-γ. p21ras activity was reduced and p38 mitogen-activated protein kinase (MAPK) was relatively spared, consistent with known biochemical characteristics of anergy. Surprisingly, calcium fluxes were also affected and the anergic phenotype could not be reversed by exogenous IL-2. Therefore, activation with a hyperstimulating non–self-ligand changes functional specificity of an autoreactive T cell without altering the TCR. This mechanism may preserve the useful reactivity of peripheral T cells to foreign antigen while eliminating responses to self

Myelin Oligodendrocyte Glycoprotein–specific T Cell Receptor Transgenic Mice Develop Spontaneous Autoimmune Optic Neuritis

Multiple sclerosis (MS) is considered to be an autoimmune disease of the central nervous system (CNS) that in many patients first presents clinically as optic neuritis. The relationship of optic neuritis to MS is not well understood. We have generated novel T cell receptor (TCR) transgenic mice specific for myelin oligodendrocyte glycoprotein (MOG). MOG-specific transgenic T cells are not deleted nor tolerized and are functionally competent. A large proportion (>30%) of MOG-specific TCR transgenic mice spontaneously develop isolated optic neuritis without any clinical nor histological evidence of experimental autoimmune encephalomyelitis (EAE). Optic neuritis without EAE could also be induced in these mice by sensitization with suboptimal doses of MOG. The predilection of these mice to develop optic neuritis is associated with higher expression of MOG in the optic nerve than in the spinal cord. These results demonstrate that clinical manifestations of CNS autoimmune disease will vary depending on the identity of the target autoantigen and that MOG-specific T cell responses are involved in the genesis of isolated optic neuritis

TGF-β Signaling Initiated in Dendritic Cells Instructs Suppressive Effects on Th17 Differentiation at the Site of Neuroinflammation

While the role of Transforming Growth Factor β (TGF-β) as an intrinsic pathway has been well established in driving de novo differentiation of Th17 cells, no study has directly assessed the capacity of TGF-β signaling initiated within dendritic cells (DCs) to regulate Th17 differentiation. The central finding of this study is the demonstration that Th17 cell fate during autoimmune inflammation is shaped by TGF-β extrinsic pathway via DCs. First, we provide evidence that TGF-β limits at the site of inflammation the differentiation of highly mature DCs as a means of restricting Th17 cell differentiation and controlling autoimmunity. Second, we demonstrate that TGF-β controls DC differentiation in the inflammatory site but not in the priming site. Third, we show that TGF-β controls DC numbers at a precursor level but not at a mature stage. While it is undisputable that TGF-β intrinsic pathway drives Th17 differentiation, our data provide the first evidence that TGF-β can restrict Th17 differentiation via DC suppression but such a control occurs in the site of inflammation, not at the site of priming. Such a demarcation of the role of TGF-β in DC lineage is unprecedented and holds serious implications vis-à-vis future DC-based therapeutic targets