Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by a wide range of clinical signs 1 . The location of lesions in the CNS is variable and is a crucial determinant of clinical outcome. Multiple sclerosis is believed to be mediated by myelinspecific T cells, but the mechanisms that determine where T cells initiate inflammation are unknown. Differences in lesion distribution have been linked to the HLA complex, suggesting that T cell specificity influences sites of inflammation2. We demonstrate that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 (T H 17) to T helper type 1 (T H 1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes. Notably, the T H 17:T H 1 ratio of infiltrating T cells determines where inflammation occurs in the CNS. Myelin-specific T cells infiltrate the meninges throughout the CNS, regardless of the T H 17:T H 1 ratio. However, T cell infiltration and inflammation in the brain parenchyma occurs only when T H 17 cells outnumber T H 1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain. In contrast, T cells showing a wide range of T H 17:T H 1 ratios induce spinal cord parenchymal inflammation. These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord.Experimental autoimmune encephalomyelitis (EAE) is an animal model that shows many similarities to multiple sclerosis3. However, rodent EAE differs from multiple sclerosis by manifesting as ascending flaccid paralysis, reflecting unexplained preferential targeting of inflammation to the spinal cord (described as classic EAE). In a small number of antigenspecific models, brain inflammation occurs (described as atypical EAE)4 -8. Interferon-γ (IFN-γ) deficiency also causes certain myelin-specific T cells to preferentially induce brain

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4+ and CD8+ T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4+ myelin-specific T cells. The role of CD8+ myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8+ T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8+ T cell–mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4+ T cell–mediated EAE. These data suggest that myelin-specific CD8+ T cells could function as effector cells in the pathogenesis of MS.

SummaryPurified CD4 + lymph node T cells were sorted into two populations on the basis of their expression of CD45RB (CD45RB hi and CD45RB 1~ and injected into congenic severe combined immunodeficient (SCID) mice. After a period of time that was dependent on the number of cells injected, the SCID mice that received CD45RBhi/CD4 + T cells developed a wasting disease that was not seen in SCID mice that received the CD4+/CD45RB 1~ cells or whole lymph node cells. At death, SCID mice that received the CD4 +/CD45RB hi cells had increased spleen and lymph node cellularity compared with normal SCID mice and SCID mice that received the CD4+/CD45RB 1~ T cells. The spleen and lymph node contained CD4 + cells and neither CD8 + nor surface immunoglobulin M-positive cells, plus a population of cells that did not express any of those markers. At necropsy, the SCID mice that received the CD4 +/CD45RB hi cells had significant hyperplasia of the intestinal mucosa with significant lymphoid cell accumulation in the lamina propria. Interestingly, mice that received mixtures of whole lymph node or purified CD4 * cells with CD4 +/CD45RB ~ cells did not develop weight loss, indicating that the unseparated CD4 + population contained cells that were capable of regulating the reactivity of the CD4 +/CD45RB hi cells. utoaggressive immunological reactivity can be driven by CD4 § thymus-derived lymphocytes. For instance, it has been demonstrated that experimental autoimmune encephalomyelitis and diabetes can be induced in normal animals by injecting them with CD4 + T cell clones or lines derived from animals with autoimmune disease of that particular tissue (1-5). Also, T cell reactivity to self-antigens can be demonstrated in normal animals by immunizing them with a closely related antigen in a unique way or by depleting them of a regulatory population (6-8). These data indicate that T cells with specificity for self-antigens exist normally, but that their reactivity is controlled by immunoregulatory mechanisms.It is well appreciated that thymus-derived lymphocytes can be categorized according to the cell surface antigens they express. This has allowed the classification ofdass I or II MHCrecognizing T cells based on their expression of CD8 or CD4 (9). Also, recent data indicate that virgin and memory T cells can be distinguished by their expression of other cell surface markers such as CD44 or CD45 (10-12). The ability to associate T cell function with the expression of a unique array of cell surface determinants is useful in studying the function of these populations in isolation as well as in defined combinations. For instance, Powrie and Mason (13) have separated CD4 + T cells based on their expression of CD45R and injected the resultant subpopulations into congenic, athymic (nude) animals. They found that nude rats injected with congenic CD45Rhi/CD4 + T cells developed wasting disease characterized by inflammatory infiltrates in many organs. Rats injected with unfractionated CD4 + cells (a mixture of CD45R hi and CD45R l~ cells) did n...

Multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, Graves disease, and systemic lupus erythematosus, are associated with an allelic variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22), which encodes the protein LYP. To model the human disease-linked variant LYP-R620W, we generated knockin mice expressing the analogous mutation, R619W, in the murine ortholog PEST domain phosphatase (PEP). In contrast with a previous report, we found that this variant exhibits normal protein stability, but significantly alters lymphocyte function. Aged knockin mice exhibited effector T cell expansion and transitional, germinal center, and age-related B cell expansion as well as the development of autoantibodies and systemic autoimmunity. Further, PEP-R619W affected B cell selection and B lineage-restricted variant expression and was sufficient to promote autoimmunity. Consistent with these features, PEP-R619W lymphocytes were hyperresponsive to antigen-receptor engagement with a distinct profile of tyrosine-phosphorylated substrates. Thus, PEP-R619W uniquely modulates T and B cell homeostasis, leading to a loss in tolerance and autoimmunity.

SUMMARY Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. The DNA binding protein CTCF regulates a diverse array of epigenetic processes and is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established. Here we show that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation, and chemically induced cancer in a broad range of tissues. Ctcf+/− tumors are characterized by increased aggressiveness including invasion, metastatic dissemination, and mixed epithelial/mesenchymal differentiation. Molecular analysis of Ctcf+/− tumors indicates that Ctcf is haploinsufficient for tumor suppression. Tissues with hemizygous loss of CTCF exhibit increased variability in CpG methylation genome-wide. These findings establish CTCF as a prominent tumor suppressor gene and point to CTCF mediated epigenetic stability as a major barrier to neoplastic progression.