Abstract
Although current vaccination strategies have been successful at preventing a variety of human diseases, attempts at vaccinating against some pathogens such as AIDS and tuberculosis (TB) have been more problematic, largely in that abnormally high numbers of antigen specific CD8+ T cells are required for protection. This study assessed the effect of temporarily dampening the chemokine receptor CXCR3 and CCR5 after vaccination on host immune responses by the administration of TAK-779, a small molecule CXCR3 and CCR5 antagonists commonly used to inhibit HIV infection. Our results showed that the use of TAK-779 enhanced memory CD8+ T cell immune responses both qualitatively and quantitatively. Treatment with TAK-779 following vaccination of an influenza virus antigen resulted in enhanced memory generation with more CD8+CD127+ memory precursor and fewer terminally differentiated effector CD8+CD69+ T cells. These memory T cells were able to become IFN-γ-secreting effector cells when re-encountered the same antigen, which can further enhance the efficacy of vaccination. The mice vaccinated in the presence of TAK-779 were better protected upon influenza virus challenge than the control. These results showed that vaccination while temporarily inhibiting chemokine receptor CXCR3 and CCR5 by TAK-779 could be a promising strategy to generate large number of protective memory CD8+ T cells.
Highlights
The ability to develop and sustainpopulations of memory T cells after infection or immunization is a hallmark of the adaptive immune response and a basis for protective vaccination against infectious disease
Studies have shown that too much inflammation, as from high levels of proinflammatory cytokines such as IL-12 and IFN-γ, favors the generation of terminally differentiated short-lived effector CD8 + T cells (SLECs). [6,7,8] On the other hand, homeostatic cytokines such as IL-7 and IL-15 promote the formation of memory precursor effector CD8 + T cells (MPECs). [9,10] In particular, recent studies have shown that CXCR3 chemokine receptors are involved in promoting CD8 + T cell commitment to an effector fate rather than a memory fate. [11,12] In addition, Kohlmeier et al found that Ccr5-/-Cxcr3-/cells exhibited markedly decreased contraction and an accumulation of massive numbers of memory CD8 + T cells after infection, where CXCR3 is primarily responsible for this phenotype
Previous studies have shown that the chemokine receptors CXCR3 and CCR5 play important roles in regulating effector CD8 + T cell contraction and memory generation after infection. [11,12,13] We examined the phenotypes of CD8 + T
Summary
The ability to develop and sustainpopulations of memory T cells after infection or immunization is a hallmark of the adaptive immune response and a basis for protective vaccination against infectious disease. Antigen-specific CD8 + T cells undergo rapid clonal expansion and differentiate into cytotoxic effector T cells, which later play an essential role in infection control through lysis of the infected cells and production of cytokines. There is compelling evidence that the inflammatory signals are crucial for clonal expansion, effector CD8 + T cell differentiation and memory development, excessive and prolonged exposure to inflammatory signals is detrimental to CXCR3 AND CCR5 INHIBITION ENHANCE VACCINATION generating potent memory CD8 + T cells. [9,10] In particular, recent studies have shown that CXCR3 chemokine receptors are involved in promoting CD8 + T cell commitment to an effector fate rather than a memory fate. Studies have shown that too much inflammation, as from high levels of proinflammatory cytokines such as IL-12 and IFN-γ, favors the generation of terminally differentiated short-lived effector CD8 + T cells (SLECs). [6,7,8] On the other hand, homeostatic cytokines such as IL-7 and IL-15 promote the formation of memory precursor effector CD8 + T cells (MPECs). [9,10] In particular, recent studies have shown that CXCR3 chemokine receptors are involved in promoting CD8 + T cell commitment to an effector fate rather than a memory fate. [11,12] In addition, Kohlmeier et al found that Ccr5-/-Cxcr3-/cells exhibited markedly decreased contraction and an accumulation of massive numbers of memory CD8 + T cells after infection, where CXCR3 is primarily responsible for this phenotype. [13] These studies underscore the role of inflammatory chemokine receptors in the generation of CD8 + T cell memory
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