The primary goal of vaccination is the establishment of protective immunity. Thus there has been significant effort put toward the identification of attributes of the immune response that are associated with optimal protection. Although the number of virus-specific cells elicited is unquestionably important, recent studies have identified an additional parameter, functional avidity, as critical in determining the efficiency of viral clearance. T-cell avidity is a measure of the sensitivity of a cell to peptide antigen. High-avidity cells are those that can recognize antigen-presenting cells (APC) bearing very low levels of peptide antigen, whereas low-avidity cells require much higher numbers of peptide major histocompatibility complex (MHC) complexes in order to become activated or exert effector function. We are only now beginning to gain insights into the molecular control of avidity and the signals required for the optimal activation, expansion, and retention of high-avidity cells in vivo. This review summarizes the current knowledge regarding CD8+ T-cell avidity and explores some of the important issues that are, as of yet, unresolved.
"The protective capacity of CD8 T cells depends on their quantity, functional properties, and anatomical distribution (15). High antigen sensitivity, otherwise referred to as functional avidity, strongly correlates with protective immunity against intracellular pathogens (16). Although T cells cannot directly alter the binding affinity of their TCR through processes like somatic hypermutation, it has been shown that monoclonal TCR-transgenic CD8 T cells can increase their functional avidity from early to late effector time points (17). "
[Show abstract][Hide abstract] ABSTRACT: Inflammatory cytokines have long been recognized to produce potent APCs to elicit robust T cell responses for protective immunity. The impact of inflammatory cytokine signaling directly on T cells, however, has only recently been appreciated. Although much remains to be learned, the CD8 T cell field has made considerable strides in understanding the effects of inflammatory cytokines throughout the CD8 T cell response. Key findings first identified IL-12 and type I interferons as "signal 3" cytokines, emphasizing their importance in generating optimal CD8 T cell responses. Separate investigations revealed another inflammatory cytokine, IL-15, to play a critical role in memory CD8 T cell maintenance. These early studies highlighted potential regulators of CD8 T cells, but were unable to provide mechanistic insight into how these inflammatory cytokines enhanced CD8 T cell-mediated immunity. Here, we describe the mechanistic advances that have been made in our lab regarding the role of "signal 3" cytokines and IL-15 in optimizing effector and memory CD8 T cell number and function. Furthermore, we assess initial progress on the role of cytokines, such as TGF-β, in generation of recently described resident memory CD8 T cell populations.
Frontiers in Immunology 06/2014; 5:295. DOI:10.3389/fimmu.2014.00295
"Antigen dose is well established as a regulator of avidity in CD8+ T cells. The inverse relationship between the level of pMHC and peptide sensitivity is evident for both the polyclonal response ,  as well as peptide induced modulation of avidity in monoclonal TCR populations , , , . While much less studied, there are data that suggest antigen dose can also impact CD4+ T cell avidity. "
[Show abstract][Hide abstract] ABSTRACT: CD4+ T cell differentiation has been shown to be regulated by the cytokine milieu present during activation as well as peptide MHC levels. However, the extent to which these two important regulatory signals work in concert to shape CD4+ T cell function has not been investigated. Using a murine OT-II transgenic TCR model of in vitro differentiation, we demonstrate that the ability of CD4+ T cells to commit to a distinct lineage, i.e. Th1 vs. Th2 vs. Th17, is restricted by the amount of peptide antigen present in the stimulating environment. In addition, whether cells succumb to inhibitory effects associated with high dose antigen is dependent on the array of cytokine signals encountered. Specifically, stimulation with high dose antigen in Th1 or Th17 conditions promoted efficient generation of functional cells, while Th2 polarizing conditions did not. Finally, we found that the peptide sensitivity of an effector cell was determined by the combined actions of cytokine and peptide level, with Th1 cells exhibiting the highest avidity, followed by Th17 and Th2 cells. Together, these data show that the interplay of antigen and cytokine signals shape both the differentiation fate and avidity setpoint of CD4+ T cells.
PLoS ONE 06/2014; 9(6):e100175. DOI:10.1371/journal.pone.0100175 · 3.23 Impact Factor
"The capacity to clear infection relies on both the quantity and the quality of responding immune cells (Haring et al., 2006; Walker et al., 2010; Zhang and Bevan, 2011). Protection by CD8 + T cells against intracellular pathogens strongly correlates with their ability to respond to low antigen density (high antigen sensitivity) (Alexander-Miller, 2005). Conversely, highly sensitive T cells could be detrimental for the host, resulting in immunopathology or autoimmunity (Amrani et al., 2000; Han et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: CD8(+) T cells confer host protection through T-cell-receptor (TCR)-mediated recognition of foreign antigens presented by infected cells. Thus, generation of CD8(+) T cell populations with high antigen sensitivity is critical for efficient pathogen clearance. Besides selection of high-affinity TCRs, the molecular mechanisms regulating the antigen sensitivity of CD8(+) T cells remain poorly defined. Herein, we have demonstrated that the antigen sensitivity of effector and memory CD8(+) T cells is dynamically regulated and can be tuned by pathogen-induced inflammatory milieux independently of the selection of cells with higher TCR affinity. Mechanistically, we have demonstrated that the signal-transduction capacity of key TCR proximal molecules is enhanced by inflammatory cytokines, which reduced the antigen density required to trigger antimicrobial functions. Dynamic tuning of CD8(+) T cell antigen sensitivity by inflammatory cytokines most likely optimizes immunity to specific pathogens while minimizing the risk of immunopathology at steady state.
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