Abstract:
The interaction of a specific antigen with its cognate antigen receptor in a quiescent T lymphocyte initiates the T-cell immune response. The recognition of antigen at the cell surface triggers second messengers to carry this information to the nucleus and to activate the expression of several genes. Before a T lymphocyte can respond to an antigen, it undergoes an antigen-independent maturation process in the thymus and other lymphoid tissues. The differentiation process involves the rearrangement of T-cell antigen receptor genes and the expression of a group of T-cell-specific surface antigens. Antigen-dependent differentiation culminates in the generation of memory cells and effector cells. Molecular events in the nucleus that initiate this differentiation in response to the detection of antigen are reviewed. Topics include biochemical requirements for T-cell activation, genes expressed during differentiation, the commitment to activation and its molecular basis (induction of interleukin 2 [IL-2] and IL-2 receptor and HIV-1 expression), and cellular oncogenes in T-cell activation (c-myc, c-fos, and others). Differentiation almost certainly proceeds through biochemical and physiologic changes that result from the sequential expression of precisely regulated genes. The fidelity of this process depends on temporal order, level of expression, and the proper physiologic context of the genes involved in differentiation. The complexity of this developmental process is illustrated by the fact that more than 70 molecules have been identified that are activated during the 2-wk period following antigenic stimulation. Gene cascades are a possible mechanism for providing temporal order in gene expression. In T-cell activation, the appearance of the nuclear regulatory factor NFAT-1, which is a major factor involved in the activation of IL-2 and possibly several other genes, seems to prompt the signals necessary for T-cell proliferation and differentiated function. A timing mechanism proposed for simplifying the activation of genes during differentiation is gene size. Because very large genes take a long time to transcribe, increased gene size could prolong the transit time of DNA polymerase, thus retarding the appearance of a regulatory gene product until it is needed for the next level of differential gene expression. Whether or not this mechanism exists in T-cell differentiation has yet to be determined. (170 Refs)
Keywords: Animal Cell Differentiation Gene Expression Human HIV-1/GENETICS/PHYSIOLOGY Interleukin-2/GENETICS/PHYSIOLOGY *Lymphocyte Transformation Mice Proto-Oncogenes Receptors, Antigen, T-Cell/PHYSIOLOGY Receptors, Interleukin-2/GENETICS/PHYSIOLOGY Regulatory Sequences, Nucleic Acid T-Lymphocytes/*PHYSIOLOGY JOURNAL ARTICLE REVIEW REVIEW, TUTORIAL 901230
M90C3736
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