Interleukin-2 receptor signaling: at the interface between tolerance and immunity

Abstract

Interleukin-2 receptor (IL-2R) signaling regulates tolerance and immunity. Here, we review recent work concerning the structure, signaling, and function of the IL-2R, emphasizing the contribution of IL-2 for T cell-dependent activity in vivo. IL-2R signaling influences two discrete aspects of immune responses by CD8(+) T cells, terminal differentiation of effector cells in primary responses, and aspects of memory recall responses. IL-2 also delivers essential signals for thymic development of regulatory T (Treg) cells and later to promote their homeostasis and function. Each of these outcomes on T effector and Treg cells requires distinct amounts of IL-2R signaling, with low IL-2R signaling sufficient for many key aspects of Treg cells. Thus, tolerance is readily maintained and favored with limited IL-2.

Figure 1. A Model of IL-2 and Its Contribution to CD8⁺ T Cell Immune Responses

After activation, CD8⁺ T cells undergo clonal expansion yielding a large population of effector cells that readily develop without IL-2. Most SLECs and TE require high amounts of IL-2 to differentiate into TE cells. MPECs are IL-2 independent and give rise to CM and EM precursors. A low amount of IL-2 during the expansion phase is required for proper development of long-lived EM, but not CM, cells. Contraction proceeds largely in the absence of IL-2R signaling. The surviving EM and CM cells form the pool CD8⁺ memory cells. Memory recall responses depend on IL-2 in two ways for optimal development of EM cells during priming and repopulation of the secondary recalled effector pool that expresses maximal functional activity. The colored heat map (white, IL-2 independent; orange, IL-2 levels, low to high) for the IL-2 requirement applies to an IL-2R signaling gradient observed through various stages of CD8⁺ T cell differentiation.

Figure 2. Model of IL-2-Dependent Control of Thymic Treg Development

IL-7 acts at either the DN or DP stage to help open Foxp3. TGFβ provides a survival signal to rescue negatively selected cells from apoptosis, permitting cells to divert to the Treg cell lineage. IL-2 acts through activation of Stat5 as a terminal developmental signal to promote maturation of immature Foxp3^lo precursor cells.

Figure 3. Model of Adaptive Homeostasis of Peripheral Treg Cells

Focusing Treg and autoreactive T cells (Tauto) though recognition of autoantigens on DCs place them in close proximity for the Treg cells to receive an IL-2-dependent signal. This interaction promotes homeostatic proliferation and survival of Treg cells and enhances aspects of their functional program. The Treg and autoreactive cells may recognize the same self antigen or distinct self antigens on the DC. Although the TCR antigenic specificity of Tauto and Treg may be identical, their fine specificity, i.e., V region sequences, may vary. Treg cells that fail to receive TCR and/or IL-2 signaling for an extended period of time undergo apoptosis. Thus, Treg cells adapt and are selectively maintained to self antigens that, in part, depend on the autoreactive T cells that they suppress.