A 33 year-old female is being followed by her neurologist for her multiple sclerosis. She was initially diagnosed with relapsing remitting subtype after an episode of visual disturbance and an episode of paralysis. In her study of autoimmune diseases she encounters the topic of lymphocyte development and comes across a question which she poses to her neurologist during a routine follow-up visit: During the process of T-lymphocyte maturation, T cell receptors of many lymphocytes demonstrate a very high-affinity interaction with MHC molecules expressed on thymic medullary epithelial and dendritic cells. What process do these lymphocytes undergo at this time?
Show Explanatory Sources
T-lymphocytes, or thymocytes, are initially produced in the bone marrow, but they migrate from that location to mature during the first trimester of gestation in the thymus. In the thymus, the processes of T-cell receptor (TCR) gene rearrangement, positive selection, negative selection, and expression of extracellular membrane markers and co-stimulatory molecules occurs. Pro-T cells arrive at the thymus as "double negative" cells – indicating that they lack both CD4 and CD8 antigens and begin their differentiation in the subcapsular zone. Next, the process of TCR beta gene rearrangement occurs with simultaneous expression of both CD4 and CD8. Once in thymic cortex, the alpha genes rearrange to produce a functional alpha-beta TCR. Subsequently, the processes of positive and negative selection occur with cells that fail either of these tests being eliminated by apoptosis.
Positive selection is the process by which only T cells expressing a TCR that is able to bind self MHC are allowed to survive. Those cells expressing a TCR that is not specific for self MHC are signaled for elimination by apoptosis. This process occurs after TCR DNA rearrangement and prior to the process of negative selection. It occurs in the thymic cortex and involves interaction of T cells with thymic cortical epithelial cells expressing self MHC (Choice D). Positive selection is responsible for development of a T cell repertoire that can recognize self.
Negative selection occurs after positive selection and is the process by which T cells possessing TCRs that bind with high affinity to self antigen or self MHC class I or II are eliminated by apoptosis. Negative selection occurs in the thymic medulla and involves interaction of the developing T cells with thymic medullary epithelial and dendritic cells. This process serves to eliminate T cells that may be overly autoreactive against self antigens and therefore may play a role in autoimmunity if not destroyed. This results in a population of T cells that have only an appropriately low affinity for self MHC molecules.
(Choice A) Affinity maturation is the process of enhancing the hypervariable region antigen binding affinity that occurs after initial binding of antigen to membrane-bound immunoglobulin on a naïve B lymphocyte and subsequent migration of that B-lymphocyte to a lymph node. Within the germinal center of the lymph node, affinity maturation is accomplished by the process of somatic hypermutation where the DNA coding for the immunoglobulin variable region is mutated randomly at a very high rate. This process results in new immunoglobulins with similar, better, or worse affinity for the antigen; only B cells expressing antibody with enhanced affinity for antigen will be selected for. This process does not occur in T-lymphocyte maturation.
(Choice B) Isotype switching is a process that occurs in naïve B-lymphocytes upon initial exposure to antigen; this process does not occur in T-lymphocyte maturation.
(Choice E) TCR DNA rearrangement is an exceedingly complex process that results in excess of 1015 different possible antigen binding sites. The process is similar to that of immunoglobulin gene rearrangement in that it involves joining of V, D, J and C regions of the TCR gene and the processes of junctional flexibility, N and P-region nucleotide addition, alternative joining of genes, and multiple peptides combining to form the intact receptor. The mature TCR is formed from joining of an a and a b protein segment, and these proteins are membrane-bound in close association with either CD4 or CD8 as well as the costimulatory CD28 and CD45.
Educational Objective:
The process of negative selection in T cell maturation is essential for eliminating T cells that bind to self MHC or self antigens with overly high affinity. This process occurs in the thymic medulla. If these cells were permitted to survive, they would likely induce immune and inflammatory reactions against self antigens leading to autoimmune disease.