Molecular differentiation of Th1,Th2, and Th17 T cells
Summary: Antigens are processed and presented to T cells by professional APCs (B cells, Mac, and DCs). Two signals are required to induce T-cell activation by APCs. The inflammatory environment shapes the activation of both T cells and APCs The function of T cells (CD4/CD8) differs primarily according to their cytokine profile.
Mechanisms of immune regulation Regulatory T cells
The principal T cell membrane proteins involved in antigen recognition and in responses to antigens are shown. The functions of these proteins fall into three groups: antigen recognition, signal transduction, and adhesion. Antigen receptors and the immunological synapse:
CD4+CD25+ cells: About 5-10% of CD4 cells. Generated in the thymus possibly via high affinity interactions with self ligands presented by thymic stromal cells. Extensive proliferation in vivo; depending on the presence of specific Ag. Their development and maintenance is highly dependent on costimulation and IL-2. Express CD25, TNFa receptor, CTLA-4, and Foxp3. MicroRNAs are involved in their differentiation.
Mechanism of action: Antigen specificity is unknown but most likely selected and respond to self Ags. Suppression is contact and also cytokine dependent (TGF-b/ IL-10). Act in tissues to control inflammation via direct effects on effector T cells or DCs.
Foxp3: Highly enriched in CD4+CD25+ cells. Its expression induces Treg activity. Targeted disruption prevents Treg development and results in autoimmune diseases in mice and humans (IPEX-immune dysregulation, polyendocrinopathy, enteropathy, X-linked). Leads to type-1 diabetes, allergy, and other. Induced by TGF-b in CD4+CD25- cells and lead to expansion of CD4+CD25+ in vitro and in vivo. Foxp3 binds other transcrition factors such as NFAT, AML1, RUNx1.
Tr1 cells: Produce IL-10 already at 4 hr after activation. Express high levels of CTLA-4. CTLA-4 dependent production of TGF-b. Express both Th1 and Th2 chemokine receptors. Proliferate poorly following activation due to autocrine effect of IL-10. IL-15 induces their proliferation as well as high levels of IL-2.
Mechanism of action: Suppress T-cell proliferation via rapid secretion of IL-10 and TGF-b. Suppression is reversed by neutralizing ab’s. Suppression of immunoglobulin by B cells. TCR ligation is essential for suppression. Suppression is more efficient with cell contact and may be antigen non-specific.