To assess the importance of B cell control of T cell differentiation, we analyzed the course of the T helper type 1 (T(H)1)-driven disease experimental autoimmune encephalomyelitis in mice with an altered B cell compartment. We found that recovery was dependent on the presence of autoantigen-reactive B cells. B cells from recovered mice produced interleukin 10 (IL-10) in response to autoantigen. With a bone marrow chimeric system, we generated mice in which IL-10 deficiency was restricted to B cells but not T cells. In the absence of IL-10 production by B cells, the pro-inflammatory type 1 immune response persisted and mice did not recover. These data show that B cell-derived IL-10 plays a key role in controlling autoimmunity.

TLR sense microbial infections, and control activation of immune responses. Dendritic cells, macrophages, and B lymphocytes express TLR and the TLR-signaling adaptor protein MyD88. The impact of TLR-activated B cells on T cell-mediated inflammation is unknown. In this study, we have used mice carrying B cell-restricted deficiencies in MyD88 or in distinct TLR to examine the impact of TLR-activated B cells on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). We demonstrate that TLR-signaling in B cells suppresses inflammatory T cell responses (both Th1 and Th17), and stimulates recovery from EAE. Only certain TLR are required on B cells for resolution of EAE, and these are dispensable for disease initiation, indicating that a category of TLR agonists preferentially triggers a suppressive function in B cells and thereby limits autoimmune disease. The TLR agonists controlling the regulatory function of B cells are provided by components of Mycobacterium tuberculosis present in the adjuvant. Thus, MyD88 signaling in B cells antagonizes MyD88 signaling in other cells, which drives differentiation of Th17 cells and is required for induction of EAE. Altogether, our data indicate that B cells link recognition of microbial products via TLR to suppression of a T cell-mediated autoimmune disease.

Clinically effective antigen-based immunotherapy must silence antigen-experienced effector T cells (Teff) driving ongoing immune pathology. Using CD4+ autoimmune Teff cells, we demonstrate that peptide immunotherapy (PIT) is strictly dependent upon sustained T cell expression of the co-inhibitory molecule PD-1. We found high levels of 5-hydroxymethylcytosine (5hmC) at the PD-1 (Pdcd1) promoter of non-tolerant T cells. 5hmC was lost in response to PIT, with DNA hypomethylation of the promoter. We identified dynamic changes in expression of the genes encoding the Ten-Eleven-Translocation (TET) proteins that are associated with the oxidative conversion 5-methylcytosine and 5hmC, during cytosine demethylation. We describe a model whereby promoter demethylation requires the co-incident expression of permissive histone modifications at the Pdcd1 promoter together with TET availability. This combination was only seen in tolerant Teff cells following PIT, but not in Teff that transiently express PD-1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation.DOI: http://dx.doi.org/10.7554/eLife.03416.001

Experimental autoimmune encephalomyelitis, an experimental murine model for multiple sclerosis, is induced by stimulation of myelin-specific T lymphocytes. Myelin oligodendrocyte glycoprotein (MOG), a minor component of myelin proteins, is a potent autoantigen which contributes extensively to the anti-myelin response. In the present work, immunoscope analyses and sequencing of the oligoclonal expansions revealed anti-MOG Va and Vb public repertoires in lymphocytes infiltrating the CNS of wild-type (WT) mice. Moreover, a subset of CNS-infiltrating CD4 + T lymphocytes bearing the public Vb8.2 segment have an inflammatory phenotype strongly suggesting that it is encephalitogenic. We then observed that, in lymph node cells of MOG-deficient and WT animals, the Va and Vb public repertoires expressed by MOG-specific T cells are identical in both strains of mice and correspond to those found in the CNS of WT animals. These findings indicate that the MOG immunodominant determinant is unable to induce tolerance by deletion, and public anti-MOG T cell repertoires are selected for, regardless of the presence of MOG in the thymus and peripheral organs. The generation of MOGKO mice has enabled researchers to probe the role of this autoantigen in shaping the autoimmune response [7]. Based on anti-MOG humoral and T cell responsiveness and encephalitogenic activity of MOG-primed T cells from these mice, we have previously found no evidence to support a gross tolerogenic effect of MOG expression. Nevertheless, only a complete picture of the autoreactive T cell repertoire can fully define the contribution of MOG to self tolerance.T cell repertoire studies have previously shown that immunodominant (ID) or subdominant peptide-specific T cells may express TCR with Va-Ja and/or Vb-Db-Jb rearrangements common to all mice or humans of the same MHC haplotype [8,9]. These recurrent rearrangements are referred to as public, while private ones were also observed, consisting of Va and Vb rearrangements that differ from one individual to another [8]. In a mouse model of tolerance to maternal Igj light chains, three public Vb-Jb rearrangements specific for a Cj peptide were found. These rearrangements are highly conserved and restored sequentially throughout life as tolerance vanished with the disappearance of Cj peptide presentation in lymphoid organs [10]. Moreover, in the B10.PL model of MBP-induced EAE, encephalitogenic T lymphocytes of Th1 phenotype express preferentially the public CDR3b, DAGGGY [11,12]. These works show that public rearrangements, found in all animals of the same MHC, can be used as molecular probes to monitor the presence of T lymphocytes specific for a well-defined epitope, and thereby provide evidence for the immunological status, tolerant or not, of the hosts. On the contrary, private repertoires cannot be used in the same way since they are expressed in one or few individuals only.Here we have precisely defined the encephalitogenic public TCR in MOG-induced EAE in WT mice. CNSinfiltrating CD4 + T cells expressing t...