An immune response requires the activation and proliferation of antigen-stimulated T cell clones. Surface interactions initiate intracellular signaling that results in the synthesis of numerous proinflammatory cytokines, survival factors, and growth factors. One of the most important growth factors is interleukin 2 (IL-2), a 15,500-kDal protein produced by activated T cells. IL-2 has both autocrine and paracrine functions. In autocrine signaling, activated T cells produce IL-2, which binds to receptors on the same cell to initiate T cell growth and proliferation. Soluble IL-2 can react with nearby activated T cells expressing IL-2 receptors (paracrine signaling) as well. IL-2 is also required for the survival and function of regulatory T cells that damper the response to self-antigens.

Signaling Pathways for Interleukin 2 Synthesis

Engagement of the TCR–HLA molecules and CD28–B7 molecules activates several signaling pathways, which culminate in the translocation of three nuclear transcription factors (NFAT, NF-κB, and an AP-1 complex consisting of Fos and Jun proteins). In the nucleus, transcription factors bind to the promoter regions of IL-2 genes, which begin the transcription of messenger ribonucleic acid (RNA) and the translation of IL-2 protein. The pathways involved in the synthesis of IL-2 are shown below.

Pathways Activated by TCR–HLA Interactions

• Ras–MAP kinase (MAPK) pathway

• Rac–JNK pathway

• PLC_γ1 calcium-dependent pathway

• PLC_γ1–DAG/PKC pathway

Pathways Activated by CD28–B7 Interactions

• PI-3 kinase pathway

Immunologic Synapse

T cell receptor (TCR)–mediated signaling is initiated by a structure known as the immunologic synapse or the supramolecular activation cluster (SMAC). The synapse is a “bull’s eye–like” structure with the engaged TCR–HLA class I or II molecules and CD28–B7 molecules clustered in the center (Figure 7-1).

Molecular clustering serves three purposes: (1) TCRs engage antigen-loaded HLA molecules with an intermediate affinity. Although these complexes only survive for short periods, they can transduce an activation signal to the nucleus. However, successful activation of T cells requires serial and sustained engagement of TCR–HLA complexes. (2) In the clustered arrangement, multiple TCRs interact with small numbers of antigen-loaded HLA molecules on antigen-presenting cells (APCs). (3) Clustering also congregates multiple cytoplasmic immuno receptor tyrosine-based activation motifs (ITAMs) near adaptor proteins, which are necessary for downstream signaling. Following the engagement of CD4 or CD8 with invariant HLA molecule domains, leukocyte-specific protein tyrosine (lck kinase) is activated and phosphorylates ITAMs. Activated ITAMs serve as “docking stations” for adaptor proteins.

Adaptor Proteins

Adaptor proteins form short-lived complexes with other proteins to transduce membrane activation signals to the major cytoplasmic signaling pathways. The most studied adaptor protein is zeta (ζ)-chain associated protein of 70 kDal (Zap-70). Phosphorylation of two ITAMs on TCR ζ-molecules creates a “docking site” for ZAP-70. CD4-activated or CD8-activated lck phosphorylates ZAP-70, which becomes an active kinase. ZAP-70 phosphorylates phospholipase C_γ1 and another adaptor protein called linker for activation of T cells (LAT).

Phosphorylated LAT serves two functions: (1) It provides a “docking site” for growth factor receptor-bound protein 2 (Grb-2) and its associated protein son of sevenless (SOS). (2) The GrB-2–SOS complex activates Ras, the initiating signal in the MAPK pathway. LAT also activates phosphokinase C_γ1 (PKC), the initiating signal for the NF–κB pathway.