Activation and Differentiation of T Cells

All organs are drained by dendritic APC (DC). These DC are normally considered as potent stimulators of T cells that prime primarily for interferon-y (IFNy) producing CD4+ and CD8+ T cells (Schuler and Steinman 1997; Schuler et al. 1997; Banchereau and Steinman 1998). DC acquire this capacity following antigen uptake while they migrate to the draining lymph nodes. This capacity in activating and stimulating T cells to become efficient effector cells, capable of mediating inflammatory immune responses and of inducing immunoglobulin production by B cells, requires a certain activation status by these APC. Thus APC co-express adhesion molecules that permit adherence of naive and activated T cells. They express a panel of co-stimulatory molecules that are required for the activation of specifically binding T cells and, in addition, they produce cytokines. Both, the sum of cell bound signals and of APC derived cytokines results not only in the stimulation and maturation of the specific T cells but also determines their differentiation. Thus, the maturation process that APC and DC undergo during their migration from the periphery to the draining lymph node will ultimately determine, whether the primary activation of T cells may lead to type 1, type 2 or Tr T cells. Depending on the functional T cell phenotype they induce, APC and DC are operationally termed DC1, DC2 or DCr (Kalinski et al. 1999; Moser and Murphy 2000) (Fig. 2).

When residing in peripheral organs, DC are continuously processing numerous antigens delivered by the local milieu. At this stage, DC have little migratory and antigen presenting capacity. Recent data suggest that the few immature and quiescent DC that migrate from peripheral organs to the draining lymph node are not capable of activating T cells to become autoaggressive. They seem either to contribute to the phenomenon of 'ignorance' or to promote the differentiation of naive but potentially autoreactive T cells towards an immunosuppressive Tr phenotype (Jonuleit et al. 2000). In sharp contrast, DC start to mature and to leave their residing site after an appropriate stimulus. Among those innate signals highly conserved so called 'pathogen associated molecular pattern' (PAMP) derived from infectious agents, such as bacterial DNA, bind to Toll-like receptors (TLR) and are increasingly recognized as most relevant activators of DC. These innate signals transform APC not only from an antigen processing towards an antigen presenting cell, capable of attracting naive and memory T cells into lymph nodes. These innate signals also determine the differentiation of APC towards either a DC1, DC2 or DCr phenotype and, in consequence, their capacity to direct the functional phenotype of the future immune response, directed against either self or foreign antigens (Banchereau and Steinman 1998; Kalinski et al. 1999; Moser and Murphy 2000). This concept was expanded by disclosing regulatory mechanisms underlaying DC induced immune responses. Thus, PAMPs present during the initial activation of DC generally instruct DC to produce

Fig. 2. Differentiation of T helper (Th) cells into either IFNy producing Th1 or IL-4 producing Th2 cells. The differentiation of Th into either Th1 or Th2 phenotypes is driven by the functional phenotype of the stimulating dendritic cells (DC), draining the site of inflammation. The 'innate' stimuli initiating both, activation and migration of the DC, also influences the differentiation of these migrating DC into either a DC1 or DC2 phenotype

Fig. 2. Differentiation of T helper (Th) cells into either IFNy producing Th1 or IL-4 producing Th2 cells. The differentiation of Th into either Th1 or Th2 phenotypes is driven by the functional phenotype of the stimulating dendritic cells (DC), draining the site of inflammation. The 'innate' stimuli initiating both, activation and migration of the DC, also influences the differentiation of these migrating DC into either a DC1 or DC2 phenotype

IL-12 and PAMPs tend to promote Th1 development leading to a proper anti-infectious immunity (Fig. 2, 3). However, some PAMPs and other signals lead to an inappropriate Th2 immunity in response to microbes (Fig. 2). Interestingly, these Th2 reactions can be switched to effective Th1 reactions, a mechanism that may also regulate autoimmunity. Paradoxically, IL-4 is a potent factor driving this switch, because IL-4 instructs activated DC to produce IL-12 and promotes Th1 cell development (Biedermann et al. 2001). These paradox functional consequences achieved by IL-4 were investigated by the sequential analysis of immune responses. Immune responses in general develop via the consecutive activation of DC and then T cells. Thus, the contrasting effects of IL-4 on immune responses with opposing functional phenotypes are a result from IL-4 signaling in early DC activation leading to a Th1 pheno-type and from IL-4 induced T cell differentiation inducing Th2 cells during a later stage.

In addition to TLR signaling, there are also PAMP and TLR independent pathways that drive T cell immunity through DC modulation. Thus, apoptotic cell material and activated NK cells can also prime DC to produce IL-12 and to induce CD8 T cell memory responses, a mechanism that may be also underlaying an activation of autoreactive lymphocytes (Mocikat et al. 2003) (Fig. 3).

Alternative activation pathways of specific immunity

PAMPs

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment