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226 Part III Immunologic Basis of Hematology

APC APC APC with the activated integrins forming the peripheral supramolecular
activation complex (pSMAC), a ring around the clustered TCRs.
MHC CD80/ CD80/ Although ligands on the APC initially direct the formation of the
CD86 CD86 IS, changes within the T cell, including reorganization of the actin
cytoskeleton, are also critical for stabilization of this structure. As
α β α β sophistication of imaging in real time has advanced and with the
TCR CD28 advent of tools to visualize smaller and smaller numbers of molecules,
it has become clear that the IS is a dynamic structure that includes not
only the TCR and integrins but also many of the signaling molecules
essential for T-cell activation.
When first described, it was assumed that the purpose of the IS is
Anergy Activation No effect to cluster the TCR together with key signaling molecules to initiate
and sustain the T-cell activation program. Recent work indicates
Fig. 21.5 TWO SIGNALS ARE REQUIRED TO ACTIVATE T CELLS. that this notion is too simplistic, because TCR signaling precedes
T-cell activation requires two signals, one through the T-cell antigen receptor IS formation. These findings led to the suggestion that the IS may
(TCR) and one mediated by a costimulatory molecule, such as CD28. An function to internalize activated receptors, thus terminating their
antigen-presenting cell (APC) will activate a T cell if it presents appropriate ability to respond. Further work indicates that under other condi-
peptide–major histocompatibility complex (MHC) to the T cell and also tions, perhaps when the avidity of the TCR for its ligand is lower,
expresses a ligand to engage CD28. If CD28 is engaged without a concomi- the IS does appear to maintain contact and allow signaling to occur.
tant TCR signal, the T cell is neither activated nor inactivated. However, if In addition to regulating TCR signaling, more recent studies suggest
a T cell is stimulated through the TCR in the absence of costimulation that another important function of the IS is to focus the release of
through CD28, then it becomes anergic, unresponsive to the initial as well cytokines from T cells toward other cells of the immune system or
as subsequent stimulations. materials from the lytic granules of cytotoxic T cells toward their
targets, thus enhancing the ability of T cells to exert their appropriate
effector functions.
phosphatidylinositol 3-kinase (PI3K), a protein that phosphorylates
PIP 2 to form phosphatidylinositol-(3,4,5)-trisphosphate (PIP 3 ).
Although the formation of PIP 3 induces broad changes within cells, T-Cell Proliferation
the PIP 3 effector pathways that have been studied most intensively
include two serine/threonine kinases: Akt, a PIP 3 -binding protein The number of naive T cells potentially responsive to any particular
responsible for regulating the metabolism of T cells to favor cell peptide antigen (the precursor frequency of the responding popula-
division, and PKCθ, a protein required for cytokine production in tion) is quite small, yet a large number of antigen-specific T cells are
T cells that is dependent upon PIP 3 generation for full activation. required to combat pathogens. Accordingly, a consequence of TCR
The importance of CD28 costimulation of T cells goes beyond its plus costimulatory receptor engagement is the clonal expansion of
requirement for T-cell activation because engagement of the TCR in an activated T cell. One outcome of the second-messenger cascades
the absence of CD28 signaling induces an impaired functional state stimulated by the TCR and CD28 is the production of IL-2, an
within T cells termed anergy (see Anergy section later in this chapter). essential cytokine for T-cell proliferation. Another outcome of TCR
Although CD28 is the prototypical and best studied costimulatory signaling is upregulation of the high-affinity receptor for IL-2, thus
receptor, a multitude of other costimulatory molecules are expressed making the activated T cell able to respond to local concentrations
on T cells and regulated in a spatiotemporal manner in response of this cytokine. Signaling through the IL-2 receptor is necessary for
to environmental cues, including CD27, inducible costimulator the proliferative response. Similarly to the TCR, the IL-2 receptor
(ICOS), and 4-1BB. These costimulatory molecules bind an array makes use of cytoplasmic PTKs (in this case members of the Janus
of ligands on other cells (primarily APCs). Stimulation of individual kinase [JAK] family) to initiate a cascade of second messengers that
costimulatory molecules can uniquely influence T-cell activation, lead ultimately to T-cell proliferation. The details of IL-2 and other
effector function, and survival. One of the mechanisms by which cytokine receptor signaling are provided in Chapter 16.
distinct costimulatory molecules play unique roles in T-cell responses
is likely due to the differential activation of discrete signaling path-
ways through their intracellular signaling domains. For instance, T-CELL DEVELOPMENT
ICOS contains a binding motif that recruits the more active subunit
of PI3K, leading to enhanced AKT signaling compared with CD28 Protective T-cell immunity requires populating the secondary lym-
activation. phoid organs with a large number of mature T cells. Unlike most
hematopoietic cells that complete the transition from progenitors
Spatial Coordination of T-Cell Receptor Signal to mature cells in the bone marrow, T cells develop primarily in the
thymus. This population collectively must possess a diverse TCR
Transduction: The Immunologic Synapse repertoire capable of recognizing the enormous number of foreign
antigens that will be encountered over life. Because the TCR binds
As the biochemical signaling events that occur following TCR engage- antigenic peptide plus amino acid residues of self-MHC molecules,
ment by peptide–MHC became known, investigators sought to it is essential that only cells with a TCR able to recognize self-MHC,
define the topography of the activation events. Sophisticated imaging albeit with limited affinity, be exported from the thymus to the
technologies were applied to visualize the contact site between the periphery. It is also critical, however, that the population of peripheral
APC and the T cell, and this interaction was modeled by visualizing T cells be restricted to those that respond to foreign antigens, and
the contact between key receptors on T cells and ligands fixed to cells possessing TCRs recognizing self-peptides plus MHC must not
a solid support. These studies revealed a stepwise reorganization be allowed to complete their developmental program. Ensuring that
of the T-cell membrane at the contact site called the immunologic only those cells with an appropriate TCR mature in the thymus
synapse (IS). The first step in IS formation is an interaction between relies heavily on many of the same TCR signal transduction events
integrins on the surface of the T cell and their ligands on the APC described earlier.
that brings the T cell and APC into close proximity. If a productive Of the T-cell lineages, those expressing the αβ TCR cells are
interaction occurs between the TCR and peptide–MHC, the next the best studied and most numerous. However, γδ T cells, another
event is clustering of TCRs in the central portion of the developing IS population that possesses an antigen receptor generated through
(the so-called central supramolecular activation complex [cSMAC]) combinatorial rearrangement of gene segments, as well as natural