Because of the remarkable expansion of antigen-specific lymphocytes at the peak of an immune response, it is predictable that once the response is over, the system must return to its steady state, called homeostasis, so that it is prepared to respond to the next infectious pathogen (see Fig. 1). During the response, the survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines such as IL-2. Once an infection is cleared and the stimuli for lymphocyte activation disappear, many of the cells that had proliferated in response to antigen are deprived of these survival signals. As a result, these cells die by apoptosis (programmed cell death). The response subsides within 1 or 2 weeks after the infection is eradicated, and the only sign that a T cell mediated immune response had occurred is the pool of surviving memory lymphocytes.

Fig1. Expansion and decline of T cell responses. The numbers of CD4+ and CD8+ T cells specific for various antigens in inbred mice and the clonal expansion and contraction during immune responses are illustrated. The numbers are approximations based on studies of model microbial and other antigens in inbred mice; in humans, the numbers of lymphocytes are approximately 1000-fold greater.

To summarize, numerous mechanisms have evolved to overcome the challenges that T cells face in the generation of a useful cell-mediated immune response:

• Naive T cells need to find the antigen. This problem is solved by APCs that capture the antigen and concentrate it in specialized lymphoid organs in the regions through which naive T cells recirculate.

 • The correct type of T lymphocytes (i.e., CD4+ helper T cells or CD8+ CTLs) must respond to antigens from the endosomal and cytosolic compartments. This selectivity is determined by the specificity of the CD4 and CD8 coreceptors for class II and class I MHC molecules and by the segregation of extracellular (vesicular) and intracellular (cytosolic) protein antigens for display by class II and class I MHC molecules, respectively.

 • T cells should respond to microbial antigens but not to harmless proteins. This preference for microbes is maintained because T cell activation requires costimulators that are induced on APCs by microbes.

 • Antigen recognition by a small number of T cells must lead to a response that is large enough to be effective. This is accomplished by robust clonal expansion after stimulation and by several amplification mechanisms induced by microbes and activated T cells themselves that enhance the response.

 • The response must be optimized to combat different types of microbes. This is accomplished largely by the development of specialized subsets of effector T cells.