Effector Fate Research Articles

The Duration of Antigenic Stimulation Determines the Fate of Naive and Effector T Cells

It is known that T cells engage antigen-presenting cells (APCs) in a stable interaction that results in sustained TCR signaling. We show here that the duration of this process is critical in determining whether T cells will be activated or deleted. Whereas naive T cells require approximately 20 hr of sustained signaling to be committed to proliferation, effector T cells become committed after only 1 hr but die following activation if antigenic stimulation is prolonged. Costimulation by anti-CD28 facilitates T cell activation by decreasing the time of commitment and by protecting T cells from death. These findings explain in quantitative terms the essential requirement for professional APCs in T cell priming and show that the duration of antigenic stimulation is the major factor determining the fate of naive and effector T cells.

Control of CD4 effector fate: transforming growth factor beta 1 and interleukin 2 synergize to prevent apoptosis and promote effector expansion.

The signals that determine the size and duration of the primary T cell immune response are not well defined. We studied CD4 T cells at an important checkpoint in their development: when they have become effectors and are ready to rapidly mediate effector functions, both via direct interaction with antigen (Ag)-presenting cells and via cytokine production. We determined the effects of specific Ag and the cytokines interleukin (IL) 2 and transforming growth factor (TGF) beta 1 on T helper cell type 2 (Th2) effector apoptosis versus expansion. Th2-polarized effector cells were generated in vitro from naive CD4 T of T cell receptor transgenic mice, and then restimulated with or without peptide Ag plus Ag-presenting cells and cytokines. In the absence of added cytokines, effector cells cultured without Ag died of apoptosis after 4-7 d. Paradoxically, Ag both induced proliferation and high levels of cytokine synthesis and accelerated effector cell death. IL-2 directly induced proliferation of effectors, supported and prolonged Ag-induced proliferation, and partially blocked apoptosis. TGF-beta did not effect proliferation or influence cytokine secretion, but it also partially blocked apoptosis. Together, IL-2 and TGF-beta synergized to almost completely block apoptosis, resulting in prolonged effector expansion and leading to the accumulation of a large pool of specific effectors. When Ag and both cytokines were present, the effector population increased 10(4)-10(5) fold over 20 d of culture. The synergy of IL-2 and TGF-beta suggests that they interfere with programmed cell death by distinct mechanisms. Since Th2 effectors are specialized to help B cells develop into antibody-secreting plasma cells, these results suggest that the availability of Ag and of the cytokines IL-2 and TGF-beta is a key factor influencing the fate of Th2 effector cells and thus the size and duration of the primary antibody response.

Cytokine regulation of effector fate and generation of polarized memory: Susan Swain, M. Croft, C. Dubey, L. Giangreco and X. Zhang, Dept of Biology, UCSD La Jolla, CA 92093

The spatial organization and differentiation of the gut immune system was studied using immunohistochemistry from Embryonic Day 15 until adulthood. Leukocyte common antigen-positive cells were detected first, followed by macrophages, B, and then T lymphocytes increasing in number and intensity of staining until adulthood. The adult mouse displays regional localization of gut immune cells with highest expression in proximal intestine, decreasing distally to ileum with the fewest cells present in colon. The role of intestinal contents, bone marrow, and thymus on maturation of the gut immune system during development was studied using an isograft model small intestines from neonatal mice were implanted subcutaneously into SCID mice and developed into morphologically normal intestine. Injected syngeneic mononuclear cells recirculated to the isografted intestine and SCID host intestine with the same regional expression as normal adult. This model is useful to define the mechanisms that establish and maintain cellular and regional differentiation of the normal gut immune system.

Correlation of cord bilirubin levels with hyperbilirubinaemia in ABO incompatibility.

We studied 91 offspring of ABO incompatible preganacies and 30 controls resulting from O--O pregnancies to test whether cord bilirubin levels could be used to predict the severity of hyperbilirubinaemia in ABO incompatibility. Blood group, direct Coombs's test, and serum bilirubin estimations were carried out on cord blood, and bilirubin estimations at 12, 24, 36, and 48 hours of life.