11.10A: Clonal Selection and Tolerance

Clonal selection and tolerance select for survival of lymphocytes that will protect the host from foreign antigens.

Learning Objectives

• Describe the importance of central and peripheral tolerance and distinguish between positive and negative clonal selection

Key Points

• Clonal selection occurs after immature lymphocytes express antigen receptors.
• Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self.
• Both developing B cells and T cells are subject to negative selection during a short period after antigen receptors are expressed.
• If, during embryonic development, it encounters its programmed antigen as part of a normal host substance (self), the lymphocyte is somehow destroyed or inactivated. This mechanism removes lymphocytes that can destroy host tissues and thereby creates tolerance for self.

Key Terms

• lymphocyte: A type of white blood cell or leukocyte that is divided into two principal groups and a null group: B-lymphocytes, which produce antibodies in the humoral immune response, T-lymphocytes, which participate in the cell-mediated immune response, and the null group, which contains natural killer cells, cytotoxic cells that participate in the innate immune response.
• antigens: In immunology, an antigen is a substance that evokes the production of one or more antibodies.
• T cells: A lymphocyte, from the thymus, that can recognise specific antigens and can activate or deactivate other immune cells.

Figure: Clonal Selection: clonal selection of the B and T lymphocytes:1. Hematopoietic stem cell 2. Immature lymphocytes with various receptors 3. “Self”-antigens from the body’s own tissues 4. Mature, inactive lymphocytes 5. Foreign antigen 6. Cloned activated lymphocytes.

Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self. The concept of central tolerance was proposed in 1959 as part of a general theory of immunity and tolerance. It was hypothesized that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance sensitive. The theory that self-tolerance is ‘learned’ during lymphocyte development was a major conceptual contribution to immunology. It was experimentally substantiated in the late 1980’s when tools to analyze lymphocyte development became available. Central tolerance is distinct from periphery tolerance in that it occurs while cells are still present in the primary lymphoid organs (thymus and bone-marrow), prior to export into the periphery. Peripheral tolerance is generated after the cells reach the periphery. Regulatory T cells can be considered both central tolerance and peripheral tolerance mechanisms, as they can be generated from self (or foreign)-reactive T cells in the thymus during T cell differentiation. However, they exert their immune suppression in the periphery on other self (or foreign)-reactive T cells.

Clonal selection occurs after immature lymphocytes express antigen receptors. The cells with useful receptors are preserved, and many potentially harmful, self antigen-reactive cells are eliminated by processes of selection induced by antigen receptor engagement. The preservation of useful specificities is called positive selection. Positive selection ensures maturation of T cells whose receptors bind weakly to self major histocompatibility complex molecules. Negative selection is the process that eliminates developing lymphocytes whose antigen receptors bind strongly to self antigens present in the lymphoid organs. Both developing B cells and T cells are subject to negative selection during a short period after antigen receptors are expressed. Negative selection of developing lymphocytes is an important mechanism for maintaining central tolerance.