T cells (T lymphocytes) are antigen-specific lymphocytes that mediate cellular immunity in the Adaptive immune system. They originate from hematopoietic stem cells in bone marrow and undergo maturation and selection in the Thymus, emerging as CD4+ or CD8+ populations that patrol lymphoid and peripheral tissues. Their antigen specificity resides in clonally unique T cell receptors (TCRs) generated by V(D)J recombination and constrained to recognize peptides bound to the Major histocompatibility complex (MHC). According to authoritative overviews, T cells are distinct from B cells in using a membrane-bound receptor and in acting primarily through cell–cell interactions rather than secreted antibodies. NCBI Bookshelf; Encyclopaedia Britannica.

Development and selection

T cell precursors arise in bone marrow and migrate to the thymic cortex, where they proliferate and express rearranged TCRs. During positive selection, thymocytes that bind self MHC receive survival signals, followed by negative selection in the medulla to delete strongly self-reactive cells; only a small fraction (roughly 5–10%) survive to exit the thymus. The autoimmune regulator AIRE, expressed by medullary thymic epithelial cells, promotes promiscuous tissue-restricted antigen expression to enforce central tolerance and support regulatory T cell induction. Encyclopaedia Britannica; Encyclopaedia Britannica; Annual Review of Immunology; Ann NY Acad Sci (PMC).

Antigen recognition and MHC restriction

The TCR is a heterodimer (usually αβ; a minority are γδ) associated with the invariant CD3 complex (εδ, εγ, and ζζ) that transmits signals after antigen engagement. CD8+ T cells recognize peptides with MHC class I, whereas CD4+ T cells recognize peptides with MHC class II; this MHC restriction arises during thymic selection and was defined experimentally in the 1970s, a discovery honored by the 1996 Nobel Prize in Physiology or Medicine. NCBI Bookshelf; NCBI Medical Microbiology; NobelPrize.org.

Activation, co‑stimulation, and the immunological synapse

Productive activation typically requires three signals at the T cell–Antigen-presenting cell interface (the immunological synapse): TCR recognition of peptide–MHC (signal 1); co‑stimulation (e.g., CD28 engaging CD80/86; signal 2); and cytokines shaping differentiation (signal 3). Early signaling is initiated by Src-family kinase Lck, phosphorylation of CD3ζ ITAMs, recruitment/activation of ZAP‑70, and phosphorylation of adaptors LAT and SLP‑76 that assemble a signalosome driving calcium–NFAT, NF‑κB, and MAPK/AP‑1 pathways and interleukin‑2 expression. Spatial organization into kinapses/synapses coordinates adhesion, polarity, and secretion. Annual Review of Immunology; Frontiers in Immunology; Blood; NCBI Bookshelf.

Inhibitory receptors modulate activation thresholds; therapeutic blockade of CTLA‑4 and PD‑1 “releases the brakes,” a principle that transformed oncology and was recognized by the 2018 Nobel Prize in Physiology or Medicine. NobelPrize.org; NobelPrize.org.

Major subsets and functions

• –CD8+ cytotoxic T lymphocytes (CTLs) identify and kill infected or malignant cells via perforin/granzyme and death receptor pathways. NIAID; Encyclopaedia Britannica.
• –CD4+ helper T cells differentiate into specialized lineages that orchestrate immunity: Th1 (intracellular microbes), Th2 (helminths/allergy), Th17 (barrier defense and neutrophil recruitment), T follicular helper (B cell help in germinal centers), and Regulatory T cell (immune restraint/tolerance). Cytokine–transcription factor networks centered on STATs and lineage “master regulators” (T‑bet, GATA‑3, RORγt, Bcl‑6, FOXP3) govern these fates. NIAID; Immunological Reviews (PubMed).
• –γδ T cells comprise a distinct subset with alternative antigen recognition and tissue localization, participating at the interface of innate and adaptive immunity. Encyclopaedia Britannica.

Memory and tissue residency

After antigen clearance, a pool of memory T cells persists with enhanced recall. Central memory (TCM; CCR7+ CD62L+), effector memory (TEM; CCR7−), and tissue‑resident memory (TRM) subsets differ in homing, persistence, and effector readiness; these properties influence vaccine design and protective immunity. Annual Review of Immunology; Journal of Immunology.

Clinical significance

• –Primary immunodeficiency: Severe combined immunodeficiency (SCID) features profound T cell deficiency and opportunistic infections; hematopoietic stem cell transplantation is the definitive therapy in many forms. MSD Manual Professional Edition.
• –Autoimmunity and tolerance: Failure of central/peripheral tolerance, including defects in AIRE‑dependent antigen display, predisposes to organ‑specific autoimmunity. Immunological Reviews; Ann NY Acad Sci (PMC).
• –Transplantation: Alloreactive T cells recognizing non‑self MHC drive rejection; modulation of co‑stimulation and T cell activation underpins immunosuppressive strategies. Annual Review of Immunology.
• –Cancer immunotherapy: Immune checkpoint inhibitors targeting CTLA‑4 and PD‑1/PD‑L1 harness T cell responses in multiple malignancies. NobelPrize.org.
• –Adoptive cellular therapy: Chimeric antigen receptor (CAR) T cells are autologous T cells engineered to recognize tumor antigens independently of MHC; in the United States, the first CAR‑T approval occurred on August 30, 2017 (tisagenlecleucel) for B‑cell ALL, followed by products for lymphomas and myeloma. U.S. FDA; U.S. FDA; U.S. FDA.

Historical landmark

The principle that T cells recognize antigenic peptides only when presented by self‑MHC (MHC restriction) was established by R. Zinkernagel and P. Doherty (1973–1975) and awarded the 1996 Nobel Prize in Physiology or Medicine. NobelPrize.org; NobelPrize.org.