18.3 T Lymphocytes and Cellular Immunity

T Lymphocyte Development and Maturation

T lymphocytes (T cells) are the central drivers of cellular immunity. They recognize and respond to specific antigens, coordinate other immune cells, and directly destroy infected or abnormal cells. Unlike antibodies that float freely in body fluids, T cells must physically interact with other cells to do their job, which is why their arm of the immune system is called cell-mediated immunity.

T cells develop from precursors that originate in the bone marrow but mature in the thymus. That maturation process is intense: the thymus tests each developing T cell to make sure it can recognize foreign antigens presented on MHC molecules without reacting against the body's own tissues. Most thymocytes actually fail these tests and die. The ones that survive emerge as mature, naive T cells ready to patrol the body.

T-Cell Maturation and Selection

T-cell maturation in the thymus involves two critical checkpoints: positive selection and negative selection. Together, they ensure T cells are both functional and safe.

1. Precursor arrival. T-cell precursors migrate from the bone marrow to the thymus, where they begin rearranging their T-cell receptor (TCR) genes through VDJ recombination. This gives each developing cell a unique TCR.

2. Double-positive stage. Early thymocytes express both CD4 and CD8 co-receptors simultaneously (called double-positive thymocytes). These cells move into the thymic cortex for the first test.

3. Positive selection (thymic cortex). Cortical epithelial cells display self-peptide–MHC complexes on their surface. Thymocytes whose TCRs bind these self-MHC molecules with moderate affinity receive survival signals and continue maturing. Thymocytes that fail to bind self-MHC (or bind too weakly) are useless and undergo apoptosis. This step ensures every surviving T cell can actually interact with MHC molecules.

4. Lineage commitment. Positively selected thymocytes become single-positive, committing to either the CD4+ lineage (if their TCR recognizes MHC class II) or the CD8+ lineage (if it recognizes MHC class I). They then migrate to the thymic medulla.

5. Negative selection (thymic medulla). Medullary epithelial cells and dendritic cells present a wide array of self-antigens. Any thymocyte whose TCR binds too strongly to self-peptide–MHC complexes is eliminated by apoptosis. This prevents self-reactive T cells from entering circulation and establishes central tolerance, the body's primary safeguard against autoimmune disease.

6. Export. Surviving mature naive T cells exit the thymus and enter the peripheral circulation, where they can encounter foreign antigens for the first time.

Genetic Recombination for Receptor Diversity

Each T cell needs a unique TCR so the immune system can collectively recognize an enormous range of pathogens. That diversity comes from somatic recombination of TCR gene segments during development.

TCR genes are built from modular segments:

• The TCR $\alpha$ chain is assembled by recombining one V (variable) segment with one J (joining) segment: $V\alpha$–$J\alpha$
• The TCR $\beta$ chain is assembled by recombining V, D (diversity), and J segments: $V\beta$–$D\beta$–$J\beta$

The enzymes RAG1 and RAG2 (recombination-activating genes) initiate this process by cutting the DNA at specific recombination signal sequences, creating double-strand breaks that allow segments to be shuffled and rejoined.

Two main sources of diversity work together:

• Combinatorial diversity: The random selection of which V, D, and J segments get joined together. With many possible segments for each, the number of combinations is huge.
• Junctional diversity: During the joining process, nucleotides are randomly added or deleted at the V-D and D-J junctions. The enzyme terminal deoxynucleotidyl transferase (TdT) adds non-templated N-nucleotides, further increasing variability.

The recombined segments form the hypervariable regions (also called CDR3) of the TCR, which are the parts that directly contact the peptide–MHC complex. Together, combinatorial and junctional diversity generate an estimated $>10^{15}$ unique TCRs, giving the adaptive immune system its hallmark antigen specificity.

T Cell Classes and Functions

CD4+ T Helper Cells

CD4+ T helper (Th) cells recognize peptide antigens presented on MHC class II molecules by antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells. Rather than killing targets directly, Th cells coordinate immune responses by secreting cytokines and providing co-stimulatory signals to other immune cells.

Different Th subsets are specialized for different types of threats:

• Th1 cells secrete IFN-$\gamma$, which activates macrophages to destroy intracellular pathogens like viruses and intracellular bacteria (e.g., Mycobacterium tuberculosis).
• Th2 cells secrete IL-4, IL-5, and IL-13, which promote B cell activation, antibody production, and isotype switching. Th2 responses are particularly important against extracellular parasites like helminths.
• Th17 cells secrete IL-17 and IL-22, recruiting neutrophils to mucosal surfaces to fight extracellular bacteria and fungi (e.g., Candida infections).
• Regulatory T cells (Tregs) suppress other T cell responses by secreting IL-10 and TGF-$\beta$. Tregs maintain peripheral tolerance and prevent autoimmunity by keeping immune responses in check after threats are cleared.

CD8+ Cytotoxic T Lymphocytes (CTLs)

CD8+ CTLs recognize peptide antigens presented on MHC class I molecules, which are found on virtually all nucleated cells. This means CTLs can detect and kill almost any cell in the body that has become infected or malignant.

CTLs kill target cells through two main mechanisms:

1. Granule-mediated killing. CTLs release cytotoxic granules containing perforin (which forms pores in the target cell membrane) and granzymes (serine proteases that enter through the pores and trigger apoptosis).
2. Cytokine secretion. CTLs secrete IFN-$\gamma$, which inhibits viral replication and upregulates MHC class I expression on nearby cells, making infected cells easier to find and kill.

Memory T Cells

After a primary immune response, most effector T cells die off, but a subset persists as memory T cells. These long-lived cells (either CD4+ or CD8+) provide the immune system with a faster, stronger response upon re-exposure to the same antigen.

Compared to naive T cells, memory T cells:

• Have a lower activation threshold (they respond to smaller amounts of antigen)
• Proliferate and differentiate into effectors more rapidly
• Produce effector cytokines sooner

Memory T cells are the reason you typically don't get sick from the same pathogen twice (think measles or chickenpox) and are the cellular basis of immunological memory, which is what makes vaccination work.

Superantigens and T-Cell Activation

Most antigens activate only a tiny fraction of T cells (less than 0.01%) because activation depends on a specific TCR matching a specific peptide–MHC complex. Superantigens break this rule.

Superantigens are toxins produced by certain bacteria and viruses that bypass normal antigen processing entirely. Instead of fitting into the peptide-binding groove, a superantigen cross-links the MHC class II molecule on an APC directly to the $V\beta$ region of the TCR on the outside of the binding groove. Because this interaction depends only on which $V\beta$ segment a T cell uses (not on its full antigen specificity), a single superantigen can activate up to 20% of all T cells at once.

This massive, nonspecific activation triggers a cytokine storm, with excessive release of IFN-$\gamma$, TNF-$\alpha$, and IL-2. The clinical consequences can be severe:

• Toxic shock syndrome (TSS): Caused by TSST-1 from Staphylococcus aureus. Presents with high fever, rash, dangerously low blood pressure, and multi-organ failure.
• Streptococcal toxic shock syndrome: Caused by streptococcal pyrogenic exotoxins (SpeA, SpeC) from Streptococcus pyogenes, also associated with scarlet fever.
• Staphylococcal food poisoning: Staphylococcal enterotoxins (SEA, SEB) can act as superantigens in addition to causing emesis.

T Cell Activation: The Two-Signal Model

A naive T cell doesn't just activate the moment its TCR contacts an antigen. Full activation requires two distinct signals, and this safeguard prevents T cells from responding inappropriately.

• Signal 1 (antigen recognition): The TCR binds a specific peptide–MHC complex on an APC. This provides antigen specificity but is not sufficient on its own.
• Signal 2 (co-stimulation): The co-stimulatory receptor CD28 on the T cell binds to CD80 (B7-1) or CD86 (B7-2) on the APC. Without this second signal, the T cell becomes anergic (functionally unresponsive) rather than activated.

Once both signals are received, the T cell undergoes clonal expansion, rapidly dividing to produce many copies of itself, all with the same antigen specificity. These clones then differentiate into effector cells that carry out cell-mediated immunity.

Key cytokines drive this process:

• IL-2 acts as an autocrine growth factor, promoting T cell proliferation and survival
• IFN-$\gamma$ activates macrophages and enhances antigen presentation
• IL-4 drives Th2 differentiation and B cell class switching

MHC and Antigen Presentation

The major histocompatibility complex (MHC) determines which peptides get displayed on cell surfaces for T cell surveillance. The two classes of MHC have distinct roles:

This division of labor means CD8+ CTLs scan for problems inside cells (viral infection, cancer), while CD4+ Th cells respond to threats captured from outside cells. Together, they cover both major routes of pathogen attack.