T cells, or T lymphocytes, are central players in the adaptive immune system, providing a highly specific defense against pathogens and abnormal cells. Their power is tightly regulated to prevent accidental self-harm. Naive T cells circulate in a dormant state until they encounter a specific threat. T cells must be “activated,” shifting them from surveillance mode into a rapid, full-scale response. This activation process requires multiple, simultaneous inputs before the immune attack can be launched.
The Two-Signal Requirement for Activation
Full T cell activation is governed by a “two-signal model,” a safeguard against autoimmunity. The first signal provides specificity, confirming the T cell has found its target. The second signal provides context, confirming the target is dangerous and warrants an attack. This dual requirement prevents T cells from reacting to self-antigens, which provide the first signal but lack the necessary danger cues for the second. If a T cell receives only the first signal, it is driven into anergy, or non-responsiveness. Anergy deactivates the T cell, providing a tolerance mechanism that protects healthy host tissue.
Signal 1: Antigen Recognition via the CD3 Complex
The first signal begins when the T Cell Receptor (TCR) recognizes a processed foreign antigen. This antigen is presented on the surface of an Antigen-Presenting Cell (APC) via a Major Histocompatibility Complex (MHC) molecule. Although the TCR is responsible for the specific binding, it lacks the machinery to transmit the activation message into the cell’s interior.
The function of translating this external binding into an internal signal falls to the CD3 complex, which is associated with the TCR. The CD3 complex is a multi-chain protein structure composed of four distinct chains: CD3-gamma, CD3-delta, CD3-epsilon, and the zeta (\(\zeta\)) chain, which typically forms a homodimer (\(\zeta\zeta\)). These chains have long cytoplasmic tails containing specialized signaling domains known as immunoreceptor tyrosine-based activation motifs (ITAMs).
Upon TCR engagement with the MHC-antigen complex, intracellular kinases rapidly phosphorylate the CD3 chains on these ITAMs. This phosphorylation acts as the initial biochemical trigger, translating the TCR’s binding into the first wave of intracellular signaling. While necessary to initiate the activation cascade, this signal is insufficient to drive a full immune response.
Signal 2: Co-Stimulation via CD28
The second signal, co-stimulation, is delivered through the receptor CD28, which is expressed on the surface of most T cells. This signal provides the context that transforms the specific antigen recognition of Signal 1 into a productive immune response. CD28 must bind to its ligands, B7-1 (CD80) or B7-2 (CD86), which are found on the surface of activated APCs.
The engagement of CD28 acts as the necessary “Go” signal, overriding the anergy state resulting from Signal 1 alone. This co-stimulatory signal significantly amplifies the biochemical cascade initiated by the CD3 complex. CD28 engagement promotes increases in glucose metabolism and triggers specific signaling pathways that lead to high levels of cytokine expression, particularly Interleukin-2 (IL-2).
The importance of CD28 is contrasted with inhibitory co-stimulatory molecules, such as CTLA-4 and PD-1, which belong to the CD28 family. These inhibitory receptors compete with CD28 for the same B7 ligands. Their binding transmits a negative, suppressive signal that helps dampen or terminate an immune response. The balance between the positive signal from CD28 and the negative signals determines the final functional fate of the T cell.
Functional Outcomes of T Cell Activation
The successful integration of both Signal 1 (via CD3) and Signal 2 (via CD28) results in profound changes in T cell behavior. A primary outcome is the rapid production of the growth factor Interleukin-2 (IL-2). IL-2 acts in an autocrine fashion; the T cell secretes it and then responds to it, driving the cell into intense proliferation.
This rapid cell division is called clonal expansion, resulting in a large population of T cells programmed to recognize the foreign antigen. Simultaneously, activated T cells undergo differentiation, transforming into various effector subsets.
Differentiation of T Cells
CD4+ T cells differentiate into helper T cell types (Th1, Th2, or Th17), each secreting a distinct set of cytokines to coordinate the immune response. CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs), which are specialized to directly kill infected or cancerous cells.
Therapeutic Targeting of the Activation Pathway
The precise control exerted by the CD3 and CD28 pathways makes them prime targets for therapeutic intervention.
Immunosuppression
In organ transplantation and autoimmune disorders, the goal is to induce immunosuppression by blocking T cell activation. Drugs like Belatacept, a modified CTLA-4 molecule, bind to the B7 ligands on APCs with high affinity, preventing activating CD28 co-stimulation. This blockade mimics the anergy signal, preventing T cells from attacking the transplanted organ or healthy host tissue.
Cancer Immunotherapy
Conversely, in cancer immunotherapy, the goal is to enhance or redirect T cell activation to fight tumors. Bispecific T cell engagers (BiTEs) are engineered antibodies that simultaneously bind to a tumor cell antigen and a T cell surface molecule, often the CD3 complex. By physically bridging the T cell and the cancer cell, these molecules deliver an artificial Signal 1, promoting activation and tumor killing. In Chimeric Antigen Receptor (CAR) T-cell therapy, the engineered receptor incorporates the intracellular signaling domains of both CD3-zeta and CD28. This ensures the engineered T cell receives both the activation and co-stimulatory signals simultaneously upon encountering a tumor antigen.