Naive T cells are found as small resting cells with condensed chromatin and scanty cytoplasm, and they synthesize little RNA or protein. On activation, they reenter the cell cycle and divide rapidly to produce large numbers of progeny as they undergo antigen-driven differentiation. Unlike effector T cells, which can produce a diversity of cytokines depending on the mature effector phenotype, naive T cells primarily produce interleukin-2 (IL-2) when activated. Based on in vitro studies, IL-2 was long thought to be required for the proliferation of naive T cells. However, in vivo studies indicate that while IL-2 can augment T-cell proliferation and survival, in many cases it is dispensable and other functions of IL-2 might be more important. In particular, IL-2 is essential for the maintenance of regulatory T cells, which do not produce their own IL-2 when activated. IL-2 also appears to affect the balance of effector and memory T cells that develop in a primary response to antigen, as will be discussed in Chapter 11.
The initial encounter with specific antigen in the presence of a co-stimulatory signal triggers entry of the T cell into the G1 phase of the cell cycle; at the same time, it also induces the synthesis of IL-2 along with the α chain of the IL-2 receptor (also known as CD25). The IL-2 receptor is composed of three chains: α, β, and γ (Fig. 9.23). Prior to activation, naive T cells express a form of the receptor composed only of the βand γ chains, which has only moderate affinity for IL-2 binding. Within hours of activation, naive T cells upregulate the expression of CD25. Association of CD25 with the βand γ heterodimer creates a receptor with a much higher affinity for IL-2, allowing the T cell to respond to very low concentrations of IL-2.
In contrast to naive T cells, regulatory T, or T , cells constitutively express
CD25, and thus the high-affinity, trimeric form of the IL-2 receptor (see Fig. 9.23). As is discussed later (see Section 9-23), it is thought that by expressing the high-affinity form of the IL-2 receptor, T cells can outcompete T cells that express only the low-affinity form of the receptor for binding of the limited quantities of IL-2 that are available early in the response to antigen. In this way, T cells act as a ‘sink’ for IL-2 to limit its availability to other cells.
However, once activated naive T cells have upregulated CD25, they form the high-affinity receptor and compete with T cells for binding of IL-2. The bind- ing of IL-2 by these activated naive T cells triggers signaling that supports their activation and differentiation, and can enhance their proliferation (Fig. 9.24). T cells activated in this way can divide up to four times a day for several days, allowing one precursor cell to give rise to thousands of clonal progeny that all bear the same antigenic receptor.