Chronic Soluble Antigen Sensitization Primes a Unique Memory/Effector T Cell Repertoire Associated with Th2 Phenotype Acquisition In Vivo

NY-ESO-1 is expressed by a broad range of human tumors and is often recognized by Abs in the sera of cancer patients with NY-ESO-1-expressing tumors. The NY-ESO-1 gene also encodes several MHC class I- and class II-restricted tumor epitopes recognized by T lymphocytes. In this study we report one novel pan-MHC class II-restricted peptide sequence, NY-ESO-1 87–111, that is capable of binding to multiple HLA-DR and HLA-DP4 molecules, including HLA-DRB1*0101, 0401, 0701, and 1101 and HLA-DPB1*0401 and 0402 molecules. We also demonstrate that peptide NY-ESO-1 87–111 stimulates Th1-type and Th-2/Th0-type CD4+ T cells and clones when presented in the context of these HLA-DR and HLA-DP4 molecules. Both bulk CD4+ T cells and CD4+ T cell clones were capable of recognizing not only peptide-pulsed APCs, but also autologous dendritic cells, either loaded with the NY-ESO-1 protein or transfected with NY-ESO-1 cDNAs. Using IFN-γ and IL-5 ELISPOT assays and PBL from patients with NY-ESO-1-expressing tumors, we observed the existence of Th1-type circulating CD4+ T cells recognizing peptide NY-ESO-1 87–111 in the context of HLA-DP4 molecules. Taken together, these data represent the first report of an HLA-DR- and HLA-DP-restricted epitope from a tumor Ag. They also support the relevance of cancer vaccine trials with peptides NY-ESO-1 87–111 in the large number of cancer patients with NY-ESO-1-expressing tumors.

Section: Discussionsupporting

confidence: 81%

One NY-ESO-1-Derived Epitope That Promiscuously Binds to Multiple HLA-DR and HLA-DP4 Molecules and Stimulates Autologous CD4+ T Cells from Patients with NY-ESO-1-Expressing Melanoma

Mandić¹,

Castelli

Janjic³

et al. 2005

“…Some T cells appear to differentiate only into one phenotype, when activated by a fixed Ag (28,(61)(62)(63), indicating an intrinsic bias during the development of Th1 and Th2 phenotype (64,65). At present there are little data regarding the role of TCR in determining the polarization of T cells toward Th17.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium smegmatisExpressing a Chimeric Protein MPT64-Proteolipid Protein (PLP) 139–151 Reorganizes the PLP-Specific T Cell Repertoire Favoring a CD8-Mediated Response and Induces a Relapsing Experimental Autoimmune Encephalomyelitis

Nicolò¹,

Sali

Sante³

et al. 2009

We infected SJL mice with a recombinant Mycobacterium smegmatis expressing a chimeric protein containing the self-epitope of proteolipid protein 139–151 (p139) fused to MPT64, a secreted protein of Mycobacterium tuberculosis (rMSp139). Infected mice developed a relapsing experimental autoimmune encephalomyelitis (EAE), showing a prevailing demyelination of the CNS, and disease severity was significantly lower in comparison with the one that follows immunization with p139. rMSp139 was not detected in lymph node or spleen in the course of clinical disease development or in the CNS during relapse. Infection with rMSp139 modified the p139-specific T cell repertoire, recruiting the spontaneous p139-specific repertoire and activating CD4+ T cells carrying the BV4 semiprivate rearrangement. T cells carrying the public BV10 rearrangement that are consistently found in the CNS during flares of disease were not activated by infection with rMSp139 because lymph node APCs infected with rMSp139 selectively fail to present the epitope for which BV10 cells are specific. Simultaneously, rMSp139 expanded p139-specific CD8+ cells more efficiently than immunization with peptide in adjuvant. SJL mice vaccinated against the CDR3 sequence of the BV10 public rearrangement reduced usage of the BV10 cells and displayed reduced symptoms during bouts of EAE. Thus, transient peripheral infection with a CNS-cross–reactive nonpathogenic Mycobacterium induces a relapsing EAE that continues long after clearance of the infectious agent. The composition of the self-reactive repertoire activated determines severity and histology of the resulting disease.

“…Each reaction was performed in duplicate. For TCR ␤-chain transcript determination, primers and probes have been described (32). Reverse and forward primers used for the SYBR Green PCR analysis of the following transcripts have also been described: TNF-␣, IFN-␥, and HPRT (33); lymphotoxin-␣ (34); CCL-1, CCL2, CCL3, CCL22, CXCL2, and CXCL9 (35).…”

Section: Quantitative Assessment Of Transcripts In the Cnsmentioning

confidence: 99%

Estrogen Receptor α Signaling in Inflammatory Leukocytes Is Dispensable for 17β-Estradiol-Mediated Inhibition of Experimental Autoimmune Encephalomyelitis

Garidou

Laffont

Douin‐Echinard

et al. 2004

Self Cite

Estrogen treatment has been shown to exert a protective effect on experimental autoimmune encephalomyelitis (EAE), and is under clinical trial for multiple sclerosis. Although it is commonly assumed that estrogens exert their effect by modulating immune functions, we show in this study that 17β-estradiol (E2) treatment can inhibit mouse EAE without affecting autoantigen-specific T cell responsiveness and type 1 cytokine production. Using mutant mice in which estrogen receptor α (ERα) has been unambiguously inactivated, we found that ERα was responsible for the E2-mediated inhibition of EAE. We next generated irradiation bone marrow chimeras in which ERα expression was selectively impaired in inflammatory T lymphocytes or was limited to the radiosensitive hemopoietic compartment. Our data show that the protective effect of E2 on clinical EAE and CNS inflammation was not dependent on ERα signaling in inflammatory T cells. Likewise, EAE development was not prevented by E2 treatment in chimeric mice that selectively expressed ERα in the systemic immune compartment. In conclusion, our data demonstrate that the beneficial effect of E2 on this autoimmune disease does not involve ERα signaling in blood-derived inflammatory cells, and indicate that ERα expressed in other tissues, such as CNS-resident microglia or endothelial cells, mediates this effect.