Following the trail from COX-2 to clotting

How a young T cell is educated may dictate its future function, according to a new report by Li et al. (page 2145). Young T cells receive survival signals through their T cell receptors during development. These signals are normally provided by epithelial cells in the thymus. But recent reports show that CD4+ thymocytes also signal to each other. When stimulated by antigen, epithelium-educated CD4+ thymocytes can become helper T cells of all varieties—T helper (Th)-1, Th2, or Th17 cells— depending largely on the surrounding cytokines. But self-educated thymocytes, Li et al. now find, fail to make this lineage choice. These cells rapidly generated both interferon (IFN)-γ and interleukin (IL)-4, even when stimulated under conditions that normally inhibit IL-4 production. A ready-to-fire IL-4 locus and preformed IL-4 mRNA in the developing cells explained their tendency to continue synthesizing IL-4. Mice whose thymocytes were forced to signal to each other to survive were less likely to develop allergic inflammation than were mice whose T cells developed normally. This protective effect might be due, the authors speculate, to the suppression of pro-allergic IL-4 by the IFNγ produced by these cells. Thus, people who have more self-educated T cells may be less allergy prone. But assessing the relative numbers of the two cell types in humans is difficult, as distinguishing surface markers have yet to be identified. The team is now investigating how T cells decide between a thymocyteand an epithelial cell–based education and how thymocyte-to-thymocyte signals set the cells up for an IL-4–producing future. A T cell transcription factor favors short-term benefits over long-term stability, according to a new study by Intlekofer et al. (page 2015). Long-term protection against pathogens by CD8+ T cells is due to a self-renewing population of central memory (TCM) cells that circulate in the lymph nodes. When they see their target antigen, these cells first rapidly proliferate, become cytotoxic, and then head out to the periphery to fight the invaders. A faster attack mode is provided by effector memory T (TEM) cells, which are already in the periphery, but these cells quickly die out. Memory T cell development requires a transcription factor called T-bet. Intlekofer et al. now find that mice lacking T-bet have plenty of TCM cells but lack the TEM pool. In normal mice, only the TEM cells expressed T-bet, suggesting that T-bet skews the balance between the two populations by driving the differentiation of activated CD8+ T cells into TEM cells. CD8+ memory T cell development also requires signals from CD4+ T cells. The team found that these signals favored the growth of CD8+ TCM cells. Mice that lacked CD4+ T cells therefore had higher numbers of TEM cells than TCM cells. This expanded TEM population had high levels of T-bet protein. Deletion of T-bet corrected this defect by restoring the numbers of self-renewing cells.