High-avidity CD8+ T cells: optimal soldiers in the war against viruses and tumors.
ABSTRACT 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.
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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.
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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. · 3.53 Impact Factor
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ABSTRACT: T-cell functional avidity is a crucial determinant for efficient pathogen clearance. Although recombinant DNA priming coupled with a vaccinia vectored vaccine (VACV) boost has been widely used to mount robust CD8(+) T cell responses, how VACV boost shapes the properties of memory CD8(+) T cells remains poorly defined. Herein, we characterize the memory CD8(+) T cells boosted by VACV and demonstrate that the intrinsic expression of MyD88 is critical for their high functional avidity. Independent of selection of clones with high-affinity TCR or of enhanced proximal TCR signaling, the VACV boost significantly increased T-cell functional avidity through a decrease in the activation threshold. VACV-induced inflammatory milieu is not sufficient for this improvement as simultaneous administration of the DNA vaccine and mock VACV had no effects on the functional avidity of memory CD8(+) T cells. Furthermore, reciprocal adoptive transfer models revealed that the intrinsic MyD88 pathway is required for instructing the functional avidity of CD8(+) T cells boosted by VACV. Taken together, the intrinsic MyD88 pathway is required for the high functional avidity of VACV-boosted CD8(+) T cells independent on TCR selection or the VACV infection-induced MyD88-mediated inflammatory milieu. The functional avidity is one of the crucial determinants of T-cell functionality. Interestingly, although it's demonstrated that DNA prime-VACV boost regimen elicits high levels of T-cell functional avidity, how VACV tunes the low avidity of CD8(+) T cells primed by DNA into higher ones in vivo is less defined. Herein, we proved that the enhancement of CD8(+) T cell avidity induced by VACV boost is mediated by the intrinsic MyD88 pathway but not MyD88-mediated inflammatory milieu, which might provide prompts in vaccine design.Journal of Virology 02/2014; · 4.65 Impact Factor