Frequencies of Neuroantigen-Specific T Cells in the Central Nervous System Versus the Immune Periphery During the Course of Experimental Allergic Encephalomyelitis

Abstract

Direct measurements of the frequency and the cytokine signature of the neuroantigen-specific effector cells in experimental allergic encephalomyelitis (EAE) are a continuing challenge. This is true for lymphoid tissues, and more importantly, for the CNS itself. Using enzyme-linked immunospot analysis (ELISPOT) assays, we followed proteolipid protein (PLP) 139–151-specific T cells engaged by active immunization of SJL mice. The total numbers of PLP139–151-specific CD4 cells were highest before disease onset. At this time, these cells resided in lymphoid and nonlymphoid tissues, but were not detected in the CNS. While the PLP139–151-specific cells reached high frequencies in the CNS during clinical EAE, in absolute numbers, less than 20% of them were present in the target organ, with the majority residing in the periphery throughout all stages of the disease. The numbers of PLP139–151-specific cells gradually declined in both compartments with time. While eventually this first wave of effector cells completely disappeared from the CNS, PLP178–191-specific cells became engaged, being detected first in the CNS. These data suggest that throughout all stages of EAE, the effector cells in the CNS are recruited from a vast peripheral reservoir, and that the second wave of effector cells is engaged while the first wave undergoes exhaustion.

Does the Frequency and Avidity Spectrum of the Neuroantigen-Specific T Cells in the Blood Mirror the Autoimmune Process in the Central Nervous System of Mice Undergoing Experimental Allergic Encephalomyelitis?

“…The CNS frequencies were considerably lower in mice with chronic EAE (Table I). These data suggest, that among the cells that infiltrate the CNS in active EAE, only a minor fraction is specific for the disease-inducing peptide, a notion supported by previous reports (18,21).…”

“…Finally, the cells were plated at various cell numbers (ranging from 5 ϫ 10 4 to 5 ϫ 10 5 per well) in HL-1 medium (BioWhittaker; supplemented with 1% glutamine) together with Ag and 5 ϫ 10 5 irradiated naive spleen cells functioning as additional APC. Cells from the spinal cord were prepared as described (18). The cells were washed twice with DMEM, counted, and plated at various numbers (from 5 ϫ 10 4 to 5 ϫ 10 5 per well in 1% glutamine-supplemented HL-1 medium) together with Ag and 5 ϫ 10 5 irradiated naive spleen cells as APCs.…”

The secretory IFN-γ response of single CD4 memory cells after activation on different antigen presenting cell types

“…Therefore, the detection and assessment of exact numbers of T cells in freshly isolated cell material such as lymphoid tissues and peripheral blood continues to be a major challenge [1,2]. This information, however, is critical for the understanding of the adaptive T cell response in immune-mediated conditions such as allergy, transplantation, autoimmunity, and immune responses to tumors.…”

T Cell Repertoire Diversity Is Required for Relapses in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

“…The sequential emergence of these public repertoires against a single epitope during EAE may be explained by the following: 1) higher avidity and/or higher precursors frequency of the public V␤8.2-J␤2.1-bearing T lymphocytes as compared with public V␤8.3-J␤1.1/V␤8.3-J␤2.3 T cells; and 2) specific elimination of V␤8.2-J␤2.1 T cells by yet undefined mechanisms. Interestingly, in PLP 139 -151-induced EAE, Targoni et al (48) showed that the vast majority of PLP 139 -151-specific CD4 T cells that appear at the onset of the disease and persist during clinical EAE are eliminated without acquiring a Th2 phenotype. The first relapse is due to intramolecular epitope spreading of the immune response characterized by the expansion of PLP 78 -191-pecific T lymphocytes (48).…”

“…Interestingly, in PLP 139 -151-induced EAE, Targoni et al (48) showed that the vast majority of PLP 139 -151-specific CD4 T cells that appear at the onset of the disease and persist during clinical EAE are eliminated without acquiring a Th2 phenotype. The first relapse is due to intramolecular epitope spreading of the immune response characterized by the expansion of PLP 78 -191-pecific T lymphocytes (48). In this model, the preferential expansion of PLP 178 -191 CD4 T cells in the CNS during the first EAE relapse may be explained by a repertoire of PLP 139 -151-specific T lymphocytes less diversified than the MOG 35-55 T cell repertoire or to higher affinity of the TCRs specific for PLP 178 -191 when compared to the low-affinity PLP 139 -151-specific T lymphocytes remaining after remission.…”