How do T cells recognize infected cells?

T cells recognize infected cells through a molecular handshake between the T cell receptor and peptide fragments of pathogen proteins displayed on major histocompatibility complex molecules. This recognition is the basis of cellular immunity, allowing the body to detect and eliminate cells that harbor viruses, certain bacteria, or intracellular parasites.

Antigen processing and presentation
Proteins from inside a cell are degraded into short peptides by cellular machinery called the proteasome and transported into the endoplasmic reticulum by TAP transporters for loading onto MHC class I molecules. These peptide–MHC class I complexes travel to the cell surface where they can be inspected by CD8 positive cytotoxic T lymphocytes. For extracellular pathogens or material captured by professional antigen-presenting cells, endosomal processing generates peptides that bind MHC class II molecules and are recognized by CD4 positive helper T cells. The principle that T cells recognize peptide only when presented by MHC molecules was first demonstrated by Rolf M. Zinkernagel and Peter C. Doherty at the University of Melbourne.

Specificity and cellular partners
The T cell receptor, a variable antigen receptor expressed on each T cell, confers precise specificity for particular peptide–MHC combinations. Mark M. Davis at Stanford University and colleagues characterized the T cell receptor and its role in antigen recognition, showing how small differences in peptide sequence or MHC can determine whether a T cell responds. Recognition is stabilized by co-receptors CD8 or CD4 binding the MHC molecule, and full activation typically requires co-stimulatory signals provided by antigen-presenting cells such as dendritic cells. Ralph M. Steinman at Rockefeller University identified dendritic cells as especially important for initiating T cell responses by presenting antigen and delivering costimulatory cues.

Causes and consequences of recognition outcomes
When a T cell recognizes a peptide–MHC complex with sufficient affinity and receives costimulatory signals, it can proliferate and carry out effector functions. Cytotoxic T cells release perforin and granzymes to kill infected cells and secrete cytokines that shape local inflammation. Helper T cells support antibody formation and direct other immune cells. Failure of recognition or inadequate costimulation can allow persistent infection or contribute to chronic disease. Conversely, inappropriate recognition of self-peptides contributes to autoimmunity, and recognition of donor MHC underlies transplant rejection.

Real-world and societal relevance
Understanding how T cells recognize infected cells underpins vaccine design, antiviral immunity, and cancer immunotherapy. Checkpoint blockade therapies that release inhibitory brakes on T cells were developed from insights into costimulatory pathways described by James P. Allison at the University of Texas MD Anderson Cancer Center, and these treatments demonstrate how modulating T cell recognition can change disease outcomes. Patterns of MHC (HLA) diversity across human populations influence susceptibility to infections and transplant compatibility, producing territorial implications for donor registries and vaccine efficacy in different regions. Environmental factors such as nutrition, chronic stress, and pollution can alter antigen presentation and T cell function, while cultural attitudes toward vaccination and medical care affect population-level protection and the success of interventions.

The molecular specificity of T cell recognition therefore connects molecular biology to clinical practice and public health, shaping how societies prevent and treat infections and how immune-based therapies are developed and implemented.