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Innate Immunity, Quality of Interactions among APCs and T Cells, and Regulatory Cells Crucial for Immune Response against Antigens

Vipin Kumar

Vipin Kumar

Innate immunity, quality of interactions among antigen presenting cells and T cells, as well as the regulatory component is crucial for the induction of an effective immune response against self or foreign antigens. Differential cytokine secretion (IFN-g vs. IL-4) by innate NK-T cells can skew T cell response in a Th1 or Th2 direction. Furthermore, the binding affinity of an antigenic determinant for the class II MHC molecules as well as the TCR avidity has critical influence on the cytokine secretion profiles of T cells (see Figure 1): antigens that bind well to MHC (a slow off rate) and recognized by a high avidity TCR, response will predominate in Th1-like cells secreting IFN-g. Whereas poor MHC-binding affinity and poor TCR avidity results in a predominant Th2-like response and the secretion of IL-4. Thus initial interactions are crucial in getting an appropriate response. The immune system also employs regulatory mechanisms at distinct levels during an immune response, for example, at the level of costimulation involving CTLA-4 etc. The phenomenon of immune exhaustion following a productive T cell response is well documented. Also there exists an important negative feed back mechanism mediated by regulatory T cells (Treg) reactive to the peptides derived from the TCR Vbeta chain expressed by effector lymphocytes (see Figure 2). The Treg are present as part of the naive TCR repertoire and maintain tolerance to self antigen, for example myelin basic protein. CD4 and CD8 Treg cells recognize distinct determinants on the TCR Vbeta chain, framework 3 region and CDR 1/2 region, respectively, in the context of class II and class I MHC molecules. Treg are primed by a professional APC following uptake of apoptotic effectors and surface display of TCR peptide-MHC complexes. The combined action of Treg results in the apoptotic depletion of activated effectors and a global deviation of immune response in a Th2 direction. This regulatory component dominantly influences whether anti-MBP responses lead to disease or remain inconsequential. How all these different components of the regulatory and the innate system are orchestrated to mount an appropriate (life vs. death) immune response would require synergy between experimental and theoretical immunologists.

 

Figure 1
Figure 1: MHC/TCR affinity

 

Figure 2
Figure 2: Four cell figure of regulation

 

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