Introduction The activation of T-cells must be tightly controlled to allow for selective proliferation of pathogen specific T-cells anergy of self-reactive T-cells prevention of autoimmune disorders Four events are required for proper T-cell activation including antigen processing and presentation by antigen presenting cells that display antigens as peptides bound to MHC migrate to draining lymph nodes specific binding of the T-cell receptor to the antigen concurrently with binding of CD4 coreceptors to MHC class II in helper T-cells binding of CD8 coreceptors to MHC class I in killer T-cells costimulation of the T-cell by antigen presenting cells through interaction between B7 (CD80/CD86) on dendritic cells CD28 on T-cells differentiation through cytokine signaling pathways at the time of activation After T-cell activation, activated cells migrate to the periphery where killer T-cells identify infected cells and release toxic substances helper T-cells undergo further differentiation into subtypes Three Signal Hypothesis Antigen presenting cells interact with naive T-cells in secondary lymphoid organs where they allow T-cells to recognize their ingested antigens they provide costimulatory input T-cells require all signals to be present in order to activate T-cells will undergo apoptosis or become anergic (state of inactivity) if they receive only one of the activation signals so that autoreactive cells can be removed benign materials are not mistakenly recognized as harmful they receive signals that the infection is cured and inflammation has subsided Three Signal Hypothesis Feature Signal 1 Signal 2 Signal 3 Function Leverage specificity of T-cell receptors to detect antigen Ensure binding to antigen presenting cell with antigen of interest Distinguish between erroneous binding of T-cell receptors and real pathogenic recognition Ensure that the recognized antigen is on an activated antigen presenting cell Convey information about the surrounding environment of the activation site Ensure proper differentiation of the activated T-cells Interacting proteins Antigen bound to MHC type I or II proteins T-cell receptor CD4 or CD8 B7 (CD80 and CD86) that are only expressed on activated antigen presenting cells CD28 IL-2 (T-cell survival signal) Diverse cytokines Cytokine receptors Associations Super antigens can artificially induce binding of T-cell receptor with MHC Induced anergy or apoptosis if not present in conjuction with signal 1 Helper T-Cell Differentiation After activation, helper T-cells further differentiate in response to cytokine signals released by the innate immune system the inflammatory environment of the activation site cross talk with other adaptive cells such as regulatory T-cells Each helper T-cell subtype differs in several ways including general function of the class signals (usually cytokines) required for differentiation secreted factors produced Helper T Cell Subtypes Feature Th1 Th2 Th17 Function Promote cell based immunity Activate macrophages and cytotoxic T-cells Promotes humoral immunity Recruits eosinophils as part of parasite defence Activate neutrophils Differentiation IFN-γ IL-12 IL-2 IL-4 IL-6 TGF-β Associations Granuloma formation Tuberculous leprosy Lepromatous leprosy IgE production by B cells Chronic inflammatory conditions Secreted Factors IFN-γ IL-2 IL-4 IL-5 IL-13 IL-17 IL-21