Human Autoreactive CD4+ T Cells from Naive CD45RA+ and Memory CD45RO+ Subsets Differ with Respect to Epitope Specificity and Functional Antigen Avidity

Muraro, Paolo A.; Pette, M.; Bielekova, Bibiana; McFarland, Henry F.; Martin, Roland

doi:10.4049/jimmunol.164.10.5474

Cited by 62 publications

(43 citation statements)

References 51 publications

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“…The observed differences appear to be more significant than those for CD4 ϩ MBP-reactive T cells seen in MS patients and controls (6,7,16). It should also be noted that unlike CD4 ϩ MBP-reactive T cells that are naive T cells expressing both CD45RA and CD45RO (30), the CD8 ϩ CTLs identified in this study belong to an Ag-experienced memory T cell subset expressing the CD45RO, but not the CD45RA, phenotype. The findings described in this study also suggest that these CD8 ϩ CTLs recognizing MBP-derived peptides may undergo in vivo activation in MS patients.…”

Section: Discussionmentioning

confidence: 99%

Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis

Zang

Rivera

et al. 2004

The Journal of Immunology

121

105

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Autoreactive T cells of CD4 and CD8 subsets recognizing myelin basic protein (MBP), a candidate myelin autoantigen, are thought to contribute to and play distinct roles in the pathogenesis of multiple sclerosis (MS). In this study we identified four MBP-derived peptides that had high binding affinity to HLA-A2 and HLA-A24 and characterized the CD8+ T cell responses and their functional properties in patients with MS. There were significantly increased CD8+ T cell responses to 9-mer MBP peptides, in particular MBP111–119 and MBP87–95 peptides that had high binding affinity to HLA-A2, in patients with MS compared with healthy individuals. The resulting CD8+ T cell lines were of the Th1 phenotype, producing TNF-α and IFN-γ and belonged to a CD45RA−/CD45RO+ memory T cell subset. Further characterization indicated that the CD8+ T cell lines obtained were stained with MHC class I tetramer (HLA-A2/MBP111–119) and exhibited specific cytotoxicity toward autologous target cells pulsed with MBP-derived peptides in the context of MHC class I molecules. These cytotoxic CD8+ T cell lines derived from MS patients recognized endogenously processed MBP and lysed COS cells transfected with genes encoding MBP and HLA-A2. These findings support the potential role of CD8+ CTLs recognizing MBP in the injury of oligodendrocytes expressing both MHC class I molecules and MBP.

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Section: Discussionmentioning

confidence: 99%

Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis

Zang

Rivera

et al. 2004

The Journal of Immunology

121

105

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“…This method is based on data that memory-originating CD4 ϩ T cells express the CD45RO, but not CD45RA. Upon Ag-induced clonal expansion their expression pattern of CD45 isoforms does not change (i.e., they remain CD45RA Ϫ /RO ϩ ) (27)(28)(29). In contrast naive-originating CD4 ϩ T cells express CD45RA, but not CD45RO.…”

Section: Flow Cytometry-based Classification Of Naive Vs Memory Origimentioning

confidence: 99%

“…In contrast naive-originating CD4 ϩ T cells express CD45RA, but not CD45RO. Upon Ag-driven expansion, they gradually down-modulate CD45RA and start up-regulating CD45RO (CD45RA ϩ /RO ϩ stage); however, several restimulation cycles are necessary to achieve the memory (CD45RA Ϫ /RO ϩ ) phenotype (27)(28)(29). Therefore, up until the second and third in vitro restimulation cycle, the naive vs memory origin of CD4 ϩ TCL can be assessed by surface CD45RA/RO expression.…”

Section: Flow Cytometry-based Classification Of Naive Vs Memory Origimentioning

confidence: 99%

“…1B, second panel). However, only several myelin epitopes contributed to the increased reactivity observed in MS patients: MBP epitopes (MBP [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] , MBP 111-129 , and MBP 146 -170 ), PLP 139 -154 , and MOG (MOG [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and MOG ) (Fig. 1B).…”

Section: Reactivity To a Set Of Myelin Ags In An Il-7-modified Primarmentioning

confidence: 99%

“…Therefore, up until the second and third in vitro restimulation cycle, the naive vs memory origin of CD4 ϩ TCL can be assessed by surface CD45RA/RO expression. Based on the time kinetics of down-modulation of CD45RA allele from the cell surface of naive T cells as analyzed in detail in our previous studies (27,28), when analyzed at the end of the second in vitro restimulation cycle (i.e., days 20 -24 proportions between 70 and 90% are classified as "indeterminate" because their origin cannot be determined with certainty. From the studied time kinetics of CD45RA and -RO expression, we can logically infer that this group contains cells originating from an in vivo-activated CD45RA ϩ /RO ϩ "doublepositive" population of "effector" T cells, but this cannot be confirmed with certainty with experimental design (27).…”

Section: Flow Cytometry-based Classification Of Naive Vs Memory Origimentioning

confidence: 99%

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Expansion and Functional Relevance of High-Avidity Myelin-Specific CD4+ T Cells in Multiple Sclerosis

Bielekova

Sung

Kadom

et al. 2004

The Journal of Immunology

Self Cite

209

183

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Multiple sclerosis (MS) is an autoimmune disease in which myelin-specific T cells are believed to play a crucial pathogenic role. Nevertheless, so far it has been extremely difficult to demonstrate differences in T cell reactivity to myelin Ag between MS patients and controls. We believe that by using unphysiologically high Ag concentrations previous studies have missed a highly relevant aspect of autoimmune responses, i.e., T cells recognizing Ag with high functional avidity. Therefore, we focused on the characterization of high-avidity myelin-specific CD4+ T cells in a large cohort of MS patients and controls that was matched demographically and with respect to expression of MHC class II alleles. We demonstrated that their frequency is significantly higher in MS patients while the numbers of control T cells specific for influenza hemagglutinin are virtually identical between the two cohorts; that high-avidity T cells are enriched for previously in vivo-activated cells and are significantly skewed toward a proinflammatory phenotype. Moreover, the immunodominant epitopes that were most discriminatory between MS patients and controls differed from those described previously and were clearly biased toward epitopes with lower predicted binding affinities to HLA-DR molecules, pointing at the importance of thymic selection for the generation of the autoimmune T cell repertoire. Correlations between selected immunological parameters and magnetic resonance imaging markers indicate that the specificity and function of these cells influences phenotypic disease expression. These data have important implications for autoimmunity research and should be considered in the development of Ag-specific therapies in MS.

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Targeting L‐Selectin Lymphocytes to Deliver Immunosuppressive Drug in Lymph Nodes for Durable Multiple Sclerosis Treatment

et al. 2023

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Inflammation induced by autoreactive CD4 + T lymphocytes is a major factor in the pathogenesis of multiple sclerosis (MS). Immunosuppressive drugs, such as FTY720, are subsequently developed to prevent the migration of CD4 + T lymphocytes to the central nervous system (CNS). However, these immunosuppressive drugs have limited accumulation in lymph nodes (LNs), resulting in poor efficacy. Here, this work develops a nanoplatform for delivering immunosuppressive drugs to LNs for durable MS treatment. Human CD47 peptide and L-selectin targeting aptamer are modified on the nanoparticles encapsulated with FTY720 (clnFTY) for self-passivation and the targeting of L-selectin on lymphocytes, a homing receptor for T-cells entering LNs. Using this natural process, clnFTY nanoparticles efficiently deliver FTY720 to LNs and delay disease progression in experimental autoimmune encephalomyelitis (EAE) mice following a single dose treatment over a 42-day observational period. Considering the daily dosing requirement of FTY720, this strategy greatly improves its therapeutic efficiency. The ability of clnFTY nanoparticles to target lymphocytes, reduce sphingosine-1-phosphate receptor 1 (S1PR1) expression, and suppress inflammatory cytokines release are demonstrated in clinical blood samples from MS patients. Taken together, this study demonstrates that targeted LNs delivery may greatly extend the treatment cycle of immunosuppressive drugs for durable MS treatment.

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Human Autoreactive CD4+ T Cells from Naive CD45RA+ and Memory CD45RO+ Subsets Differ with Respect to Epitope Specificity and Functional Antigen Avidity

Cited by 62 publications

References 51 publications

Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis

Increased CD8+ Cytotoxic T Cell Responses to Myelin Basic Protein in Multiple Sclerosis

Expansion and Functional Relevance of High-Avidity Myelin-Specific CD4+ T Cells in Multiple Sclerosis

Targeting L‐Selectin Lymphocytes to Deliver Immunosuppressive Drug in Lymph Nodes for Durable Multiple Sclerosis Treatment

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