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Review
. 2004 Jun;78(11):5535-45.
doi: 10.1128/JVI.78.11.5535-5545.2004.

Memory CD8 T-cell differentiation during viral infection

E John Wherry  1 , Rafi Ahmed
Affiliations
Review

Memory CD8 T-cell differentiation during viral infection

E John Wherry et al. J Virol. 2004 Jun.
No abstract available

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
(A) The dynamics of a CD8 T-cell response to acute infection. A CD8 T-cell response to an acute viral infection undergoes an expansion phase, culminating in the generation of effector CD8 T cells and viral clearance. The expansion phase is followed by a death phase, when 90 to 95% of the effector T cells die. The surviving 5 to 10% of the effector CD8 T-cell pool further differentiates and generates a memory T-cell population that is maintained long term in the absence of antigen. (B) Memory CD8 T-cell generation is linear and progressive. Antigenic stimulation causes naïve CD8 T cells to proliferate and acquire effector functions. The effector T cells that survive the death phase further differentiate, giving rise to memory T cells that continue to differentiate in the absence of antigen and acquire the ability to persist in the absence of antigen via homeostatic turnover. (C) Memory CD8 T-cell properties that change during the naïve → effector → memory transition are listed. (D) Phenotypic changes that occur during the naïve → effector → memory transition are listed, including differences between the effector memory (TEM) and central memory (TCM) subsets of memory CD8 T cells. Int, intermediate.
FIG. 2.
FIG. 2.
Model for hierarchical exhaustion of CD8 T-cell functions during chronic viral infections. Persisting virus can result in various levels of CD8 T-cell function during chronic infections. If the level or frequency of antigenic stimulation of T cells is low and CD4 help is sufficient, functional CD8 T cells can coexist with persisting virus. However, as the level or frequency of antigenic stimulation increases and/or CD4 help decreases, virus-specific CD8 T cells progressively lose functional properties. Partial exhaustion I is the stage when CD8 T cells have lost the capacity to produce IL-2 and when TNF-α production begins to be impaired. Ex vivo lytic capacity may also be reduced at this stage. Partial exhaustion II occurs when CD8 T cells begin to lose the ability to synthesize IFN-γ and fail to produce IL-2 or TNF-α following antigenic stimulation. Full exhaustion, a state when CD8 T cells lack all effector functions (IFN-γ, TNF-α, IL-2, and ex vivo lytic activity) following antigenic stimulation, can occur when the antigen load is high and/or CD4 help is low. Finally, physical deletion of antigen-specific T cells can occur if epitope presentation to T cells is high and/or sustained. T-cell proliferative potential in response to antigenic stimulation also likely decreases during the outlined stages of functional exhaustion as other functions are impaired. This hierarchical loss of function is dramatically influenced by the level and/or duration of antigenic stimulation experienced by T cells during chronic infections. Further, the stage of exhaustion is also related to CD4 help, since the absence of CD4 help results in more extreme loss of function by CD8 T cells during chronic infections.
FIG. 3.
FIG. 3.
CD4 help for CD8 T-cell responses during acute viral infections. In the presence of adequate CD4 help during acute infection, efficient effector CD8 T-cell responses are generated and subsequently form memory CD8 T cells that can persist long term. Upon reinfection, these “helped” memory CD8 T cells undergo efficient recall responses generating a large pool of secondary effector T cells. In the absence of CD4 help during primary infection, CD8 T cells still generate a population of effector T cells, and these effectors can populate a memory T-cell pool. However, these “unhelped” CD8 T cells respond poorly to restimulation with antigen and generate a suboptimal population of secondary effectors following reinfection compared to that of helped CD8 T cells. It will be important to determine whether memory CD8 T-cell differentiation occurs normally in unhelped CD8 T cells. In addition, the importance of long-term maintenance of CD4 responses during chronic infections has long been appreciated, but precisely how CD4 T cells help ongoing CD8 T-cell responses during persisting infections is not well understood.
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