Cytokines and the inception of CD8 T cell responses

Abstract

The activation and differentiation of CD8 T cells is a necessary first step that endows these cells with the phenotypic and functional properties required for the control of intracellular pathogens. The induction of the CD8 T cell responses typically results in the development of a massive overall population of effector cells, comprising both highly functional but short-lived terminally differentiated cells, as well as a smaller subset of precursors that are predisposed to survive and transition into the memory T cell pool. In this review, we discuss how inflammatory cytokines and IL-2 bias the initial response towards short-lived effector generation, and also highlight the potential counterbalancing role of IL-21.

Figure 1

Naïve CD8 T cells have the potential to differentiate into both short-lived effectors and memory precursors following activation. Short-lived effector cells are commonly defined as CD127^lo, KLRG-1^hi and express a panel of transcription factors, which promote effector activities but limit their proliferative capacity and survival. By contrast, memory precursors are typically CD127^hi, KLRG-1^lo. These cells also have certain effector properties including the ability to produce IFN-γ, but unlike their short-lived counterparts they are more likely to survive the downregulation of the response and transition into memory populations, which persist over time and help confer long-lived immunological protection. Different priming strategies and infections can skew the developmental process in either direction, which is determined by various factors including duration of stimulation and the composition of the cytokine milieu. This likely results in a spectrum of differentiated states, ranging from terminally differentiated effector cells to memory precursors.

Figure 2

Inflammatory cytokines, type I IFN, IL-2, and IL-21, dictate the balance between short-lived effector and memory precursor generation. Infections often cause increases in the levels of the pro-inflammatory cytokine IL-12 and/or type I IFN, which in conjunction with antigenic activation and costimulation, promote the differentiation of short-lived effector cells but restrict the formation of memory precursors. High levels of IL-2 similarly enforce short-lived effector formation, whereas the related cytokine IL-21 potentially plays a less well defined role in restricting the terminal differentiation of the T cell population.

Figure 3

IL-2 levels and CD25 expression influence the short-lived effector versus memory precursor fate decision. IL-2 induces the expression of CD25, a component of cognate receptor for this cytokine. This allows the activated cells to receive longer and greater IL-2 signals which drive their differentiation towards a short-lived effector state. Lower amounts of IL-2, which may occur if CD4 T cells are defective or not available, as well as the loss of CD25 expression limits the terminal differentiation of the responding cells and favors the formation of memory precursors.