The contribution of CDS cytotoxic T lymphocytes (CTL) to the eradication of viral infections has been well documented. Recent studies from our lab and others have demonstrated that the functional avidity of a CTL, as defined by the sensitivity to peptide antigen, is a major determinant of the efficacy for viral clearance in vivo. The mechanisms which control the avidity of an individual CTL, as well as the activation and expansion of high avidity CTL in vivo, are fundamental issues in immunology which have important implications for the design of vaccine constructs and immunotherapeutics. Presently, the mechanism by which avidity is established in an individual T cell is largely undefined. Further whether avidity is an inherent property or can be modulated in response to environmental signals is unknown. In our analysis of high and low avidity lines generated from TCR transgenic mice, we made the surprising observation that low avidity cells express CD8alpha/beta homodimers in addition to CD8alpha/beta heterodimers. Expression of CD8alphaa/alpha may reduce the efficiency with which these cells transduce TCR signals, given the reduced localization of CD8alpha/alpha and its associated kinase, Lck, to lipid raft resident TCR. Using sorted populations of cells from TCR transgenic mice, we have found that CD8P expression at the cell surface is regulated as a result of the level of peptide antigen encountered, consistent with the hypothesis that avidity in modulated by antigen encounter.
In aim one we will address a number of critical questions regarding the control of avidity including how CDSalpha and beta expression are modulated by antigen encounter, when avidity becomes fixed in effector cells, how the level of peptide antigen alters the association of CDS with the TCR complex, and whether memory cells are capable of CDS modulation in response to the level of presented peptide antigen. Further expression of alpha and/or beta will be altered by retroviral transduction and CDS protein expression will be studied to determine how CDS expression is controlled and its result on function.
In aim two we will extend our in vitro studies of the effect of differential antigen presentation to the in vivo activation of CD8+ T cells following viral infection. This will be accomplished through use of a panel of vaccinia viruses which result in high, intermediate, or low levels of presented antigen. The results from these studies will significantly increase of understanding of the control of functional avidity and the activation/expansion of high avidity cells in vivo and may provide novel insights into the design of improved vaccine strategies.
|Holbrook, Beth C; Yammani, Rama D; Blevins, Lance K et al. (2013) In vivo modulation of avidity in highly sensitive CD8(+) effector T cells following viral infection. Viral Immunol 26:302-13|
|Amoah, Samuel; Holbrook, Beth C; Yammani, Rama D et al. (2013) High viral burden restricts short-lived effector cell number at late times postinfection through increased natural regulatory T cell expansion. J Immunol 190:5020-9|
|Amoah, Samuel; Yammani, Rama D; Grayson, Jason M et al. (2012) Changes in functional but not structural avidity during differentiation of CD8+ effector cells in vivo after virus infection. J Immunol 189:638-45|
|Sharma, Sharad K; Alexander-Miller, Martha A (2011) Increased sensitivity to antigen in high avidity CD8(+) T cells results from augmented membrane proximal T-cell receptor signal transduction. Immunology 133:307-17|
|Kroger, Charles J; Amoah, Samuel; Alexander-Miller, Martha A (2008) Cutting edge: Dendritic cells prime a high avidity CTL response independent of the level of presented antigen. J Immunol 180:5784-8|
|Kroger, Charles J; Alexander-Miller, Martha A (2007) Dose-dependent modulation of CD8 and functional avidity as a result of peptide encounter. Immunology 122:167-78|
|Kroger, Charles J; Alexander-Miller, Martha A (2007) Cutting edge: CD8+ T cell clones possess the potential to differentiate into both high- and low-avidity effector cells. J Immunol 179:748-51|
|Gray, Peter M; Arimilli, Subhashini; Palmer, Ellen M et al. (2005) Altered function in CD8+ T cells following paramyxovirus infection of the respiratory tract. J Virol 79:3339-49|
|Cawthon, Andrew G; Kroger, Charles J; Alexander-Miller, Martha A (2004) High avidity CD8+ T cells generated from CD28-deficient or wildtype mice exhibit a differential dependence on lipid raft integrity for activation. Cell Immunol 227:148-55|
|Gray, Peter M; Parks, Griffith D; Alexander-Miller, Martha A (2003) High avidity CD8+ T cells are the initial population elicited following viral infection of the respiratory tract. J Immunol 170:174-81|
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