MCB9728332 Punt, Jennifer RUI: Why Can't CD4+ CD8+ Thymocytes be Stimulated to Proliferate? Lay Summary A basic question in immunology is why immature T lymphocytes respond so differently to stimulation compared to their mature descendants. Mature T lymphocytes are important participants in the immune response because they protect the body from viruses and tumors by (a) recognizing and attacking abnormal or infected cells and (b) alerting other parts of the immune system to their presence. T cells recognize threatening cells by binding foreign protein (antigen) to receptors, called T cell receptors, on their surfaces. Every T lymphocyte expresses a different T cell receptor. Therefore the large population of T cells in the body can collectively defend the body against a large range of threatening cells. New T cells with new receptors are generated every day as T cells develop from immature precursors in an organ called the thymus. The receptors expressed by the immature cells (called thymocytes) are randomly generated. Because each new thymocyte expresses a brand new receptor, the cell must be tested for its suitability before being released into the body. The screening for suitable cells occurs at a pivotal stage of development, the "double positive" (DP) stage, so-called because these cells express two key proteins, CD4 and CD8. DP thymocytes are the immediate precursors of mature T cells. However, the vast majority of DP thymocytes are never selected to become mature thymocytes because their receptors are deemed useless or directed against a normal antigen of the body. The fate of the DP cells during this screening process is governed almost entirely by the signals they receive from their new receptors. Interestingly, DP thymocytes interpret receptor signals very differently from mature T cells. When mature T cells receive a strong signal through their receptor, they become activated and start to divide. When immature DP thymocytes receive the same signal, they also b ecome activated but do not divide. Nothing, in fact, seems to induce cells at this early stage of development to multiply. The reason for this is not yet known. To determine why DP thymocytes fail to divide in response to T cell receptor signals, these studies will compare the molecular machinery responsible for cell division in immature DP and mature T cells. These studies will also test the possibility that the inability of a DP thymocyte to divide may be critical to the success of this screening process which fundamentally shapes the immune response.
