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The success of vaccination is directly or indirectly based on the specificity of antigen recognition by T lymphocytes, their efficient activation and expansion, and the generation of vaccine-specific effector and memory cells. These traits are largely dependent on the correct assembly and expression of sufficient number of functional TCR/CD3 complexes in the cell surface. In this review, some of the genetic and epigenetic factors that determine the correct assembly and structure of the TCR/CD3 complex are summarized. Those physiologic or pathologic factors leading to natural variations, or pathologic alterations of the standard that might lead to poor response to vaccination and that could give some possibilities to pharmacological intervention are emphasized.