These concerns have provided an important impetus to understanding in detail the mechanisms underlying the behavior not only of murine TMP cells but also TEM cells following transfer to allogeneic BMT recipients.

Three broad aspects of memory T cells, namely their trafficking potential, Panobinostat mouse TCR repertoire, and intrinsic properties independent of specificity, have been evaluated for their relevance to GVHD induction (Fig. 1). The first concept is based on the premise that the initiation of GVHD requires the activation of T cells by APCs within specialized SLO compartments such as the spleen, Peyer’s patches (PPs) or lymph nodes (LNs) 9 (Fig. 1A). In this model, TMP cells with a CD44+CD62L− phenotype would fail to induce GVHD because they lack the homing receptors, such as CD62L or CCR7, required for accessing LNs; however, elegant experiments involving blocking antibodies

or recipients lacking Peyer’s patches or LNs (aly/aly or lymphotoxin α chain knockout mice), with or without additional splenectomy, have indicated a surprising and considerable redundancy in the requirement for SLOs in the initiation phase of GVHD 19, 20. Furthermore, neither the absence of CD62L on transferred CD4+ TN cells nor the absence of its ligand, peripheral node addressin, on the high endothelial venules (HEVs) in recipient mice were found to influence the capacity of TN to induce GVHD 19. Conversely, enforced constitutive expression of CD62L in CD4+ TMP cells failed to confer a greater ability of these cells to induce GVHD 19. Together, these Kinase Inhibitor Library price 3-oxoacyl-(acyl-carrier-protein) reductase data do not provide a compelling case that differences in homing receptor expression between TMP and TN cells are of major relevance for GVHD. A second

model invokes the concept that, compared with TN cells, murine TMP cell populations lack precursors with specificity for host antigens (Fig. 1B). Under these circumstances, the lack of GVHD following transfer of TMP cells would reflect a lower precursor frequency for alloantigen. This hypothesis is tested directly by Mark and Warren Shlomchik and colleagues in their article published in this issue of European Journal of Immunology4. The authors reasoned that if the lack of allospecific precursors within the memory CD4+ T-cell population was directly responsible for their reduced capacity to induce GVHD, then manipulations that boosted the frequency of alloreactive clones within the population would reverse this deficiency. The experimental approach taken was to first prime donor CD4+ T cells against host alloantigens in vivo by transferring them to irradiated MHC-matched, multiple minor H antigen-mismatched hosts; the recipient mice readily developed GVHD in the skin and colon. After 5 wk, donor CD44+CD25−CD4+ T cells were isolated from the hosts with GVHD and then “parked” for 7–8 wk in syngeneic RAG−/− hosts.