More on T-Lymphocyte Subpopulations

MORE ON T-LYMPHOCYTE SUBPOPULATIONS

1) Effector T-Helper Cell Subtypes

Following maturation in the thymus, mature but naive CD4+ helper T-cells access the systemic blood and lymphatic circulations. In this naive state they have yet to be stimulated by antigen. The antigen-driven activation signals involve initially TCR interactions with MHC presented peptide and subsequent CD3 activation. This is followed by the interaction of a variety of costimulatory molecules on the surface of the APC (e.g. CD80, CD86) with surface receptors (e.g. CD28) on the helper T-cell. Once the helper T-cell is activated it can proliferate in an autocrine or paracrine fashion driven by secreted IL-2. These proliferating helper T-cells will then differentiate depending on their cytokine environment; for example, IFN-γ and IL-12 drive the differentiation to a T_H1 subpopulation of cells while IL-4 drives the differentiation to a T_H2 subpopulation of cells.

Apart from IL-2 the main cytokines produced by T_H1 cells are IFNγ and TNFβ, and the main cell partner for T_H1 cells are the APCs. The T_H1 cells classically promote cell-mediated immune responses maximizing the effectiveness of APCs and the proliferation of cytotoxic CD8+ T-cells. Apart from IL-2 the main cytokines produced by T_H2 cells are IL-4, 5,6,10 and 13, while the main cell partner for T_H2 cells is the B-cell. The T_H2 cells classically promote the humoral immune responses stimulating B-cells to proliferate to undergo Ig class switching and increase Ig production and secretion.

The above model of helper T-cell subpopulations and how various cytokines can serve to promote the differentiation pathway to either T_H1 or T_H2 phenotype is recognized to be an oversimplification. However, the basic model serves to emphasize that distinct populations of helper T-cells exist that fulfil many different and varied functions.

2) T-Regulatory Cells

T-regulatory cells (Tregs) are a subset of T lymphocytes that serve an immune suppressor function leading to peripheral tolerance to selfor foreign antigens. Tregs are characterized by a CD4+/CD8− phenotype, but among a number of other identity markers that these cells display the expression of the Foxp3 transcription factor is the main distinguishing feature. Tregs are distinct from those effector T-cells which are induced to switch to secrete immunosuppressive cytokines as a typical immune response progresses with time from an immunostimulatory to immunoinhibitory character. The Tregs represent approximately 10% of all CD4+ T-cells and can acquire the immunosuppressive phenotype in the thymus or via induction in the periphery. In the thymus this subset of CD4+ T-cells are positively induced by interactions with MHC molecules and the recognition of agonist peptide. This contrasts to the situation for effector T-cells where TCR recognition in the thymus of MHC-presented peptide normally triggers the positive deletion of the affected T-cell. In particular TGF appears particularly important for the expression of the Tregs phenotype while IL-2 as the key T-cell mitogen is also important.

Tregs essentially serve to suppress immune responses of effector T-cells, effector B-cells and APCs leading to peripheral immune tolerance. Direct cell–cell contact as well as cytokine signalling are mechanisms important in mediating their actions. These cells play an important role in self-limiting immune responses. Tregs display a number of disease associations, with decreased numbers of Tregs or reduced function in a range of autoimmune diseases. Tregs also appear to fulfil a role in the active immune evasion of tumours, with the experimental depletion of Tregs improving natural antitumour immunity and effectiveness of active immunotherapy.

3) γδ T-cells

The vast majority of T-cells possess a TCR comprised of two polypeptide chains, a single α-chain and a single β-chain. γδ T-cells possess a TCR made of a single γ-chain and a single δ-chain. The antigenic molecules or ligands that activate γδ T-cells remain essentially unknown, although they appear not to require antigen processing or MHC presentation. These cells have characteristics of both innate and adaptive immune cells possessing a TCR, but also undergoing early activation capable of phagocytosis and rapid production of cytokines that regulate inflammation and pathogen removal.