Role of Endothelial TLR4 for Neutrophil Recruitment into Central Nervous System Microvessels in Systemic Inflammation
Open Access
- 15 October 2009
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 183 (8), 5244-5250
- https://doi.org/10.4049/jimmunol.0901309
Abstract
Immunotherapy of cancer is often performed with altered “analog” peptide Ags optimized for HLA class I binding, resulting in enhanced immunogenicity, but the induced T cell responses require further evaluation. Recently, we demonstrated fine specificity differences and enhanced recognition of naturally presented Ag by T cells after vaccination with natural Melan-A/MART-1 peptide, as compared with analog peptide. In this study, we compared the TCR primary structures of 1489 HLA-A*0201/Melan-A26–35-specific CD8 T cells derived from both cohorts of patients. Although a strong preference for TRAV12-2 segment usage was present in nearly all patients, usage of particular TRAJ gene segments and CDR3α composition differed slightly after vaccination with natural vs analog peptide. Moreover, TCR β-chain repertoires were broader after natural than analog peptide vaccination. In all patients, we observed a marked conservation of the CDR3β amino acid composition with recurrent sequences centered on a glycyl-leucyl/valyl/alanyl-glycyl motif. In contrast to viral-specific TCR repertoires, such “public” motifs were primarily expressed by nondominant T cell clonotypes, which contrasted with “private” CDR3β signatures frequently found in T cell clonotypes that dominated repertoires of individual patients. Interestingly, no differences in functional avidity were observed between public and private T cell clonotypes. Collectively, our data indicate that T cell repertoires generated against natural or analog Melan-A peptide exhibited slightly distinct but otherwise overlapping and structurally conserved TCR features, suggesting that the differences in binding affinity/avidity of TCRs toward pMHC observed in the two cohorts of patients are caused by subtle structural TCR variations.Keywords
This publication has 24 references indexed in Scilit:
- TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1Neurochemistry International, 2007
- The Role of Platelets in Leukocyte Recruitment in Chronic Contact Hypersensitivity Induced by Repeated ElicitationThe American Journal of Pathology, 2007
- Systemic Inflammatory Stimulus Potentiates the Acute Phase and CXC Chemokine Responses to Experimental Stroke and Exacerbates Brain Damage via Interleukin-1- and Neutrophil-Dependent MechanismsJournal of Neuroscience, 2007
- Immune complexes alter cerebral microvessel permeability: roles of complement and leukocyte adhesionAmerican Journal of Physiology-Heart and Circulatory Physiology, 2006
- Platelets express functional Toll-like receptor-4Blood, 2005
- CXCR2 is essential for maximal neutrophil recruitment and methacholine responsiveness after ozone exposureAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2005
- Sepsis associated encephalopathy (SAE): a reviewFrontiers in Bioscience-Landmark, 2004
- Three or more routes for leukocyte migration into the central nervous systemNature Reviews Immunology, 2003
- Multifocal necrotizing leukoencephalopathy in septic shockCritical Care Medicine, 2002
- Leukocyte traffic in the central nervous system: the participants and their rolesSeminars in Immunology, 1999