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In order to effectively perceive the huge diversity of antigenic determinants to which it is confronted, the immune system uses referring internal images from self. The major histocompatibility complex constitutes the main reference to self, essential to the operating system of T and NK lymphocytes. It is involved in shaping the T operating repertoire in the thymus, where each differentiating thymocyte, with its TCR interacting with the MHC-peptide self complexes exposed by thymic presenting cells, should answer to both questions: Is it really necessary (positive selection) Is not dangerous (negative selection)? Once in periphery, naive T lymphocytes will undergo an homeostatic control helping their survival through the same contacts between TCR and MHC-peptide self complex than those which allowed the thymic positive selection. In a more hypothetic way, it is possible that contact between a T lymphocyte and the rare foreign MHC-peptide complexes spread at the surface of antigen presenting cell, is not sufficient to initiate its activation. Some arguments exist to involve the MHC-peptide self complexes themselves in the activation process.Finally, the MHC also constitutes a quality referential for the NK lymphocytes. When a somatic cell, infected by a virus or transformed, repress the expression of one or more of its class I HLA alleles, this absence of the self is perceived by the NK lymphocytes which proceed to its elimination through cytolysis. This disposition to sanction the non-self is also used for therapeutic purpose in the case of a non HLA identical allogenic hematopoi¨etic stem cells graft. [Copyright &y& Elsevier]