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An endogenous suppressor of HIV-1 transcription
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Naive T cell homeostasis
Control of peripheral naive T cell homeostasis is mediated through contact with self-MHC/peptide complexes and IL-7. It is not known whether TCR affinity plays a role in homeostatic proliferation. Kieper et al. (p. 40 ) found that proliferation in irradiated hosts of T cell lines transgenic (Tg) for TCRs of different affinities for self-MHC/peptide ligands varied inversely with the density of TCR and directly with the level of CD5 expression. Coinjection of a low dose of bystander wild-type CD8+ T cells or of low affinity Tg TCR CD8+ T cells before injection of a mixture of the TCR Tg and wild-type cells suppressed proliferation of the autologous injected cells. Suppression of the highest affinity cells occurred only with a higher dose of high affinity TCR Tg bystander cells. Proliferation of the high affinity cells 4 wk after injection of the mixture of cells into unirradiated hosts was lowest in the autologous host and highest in the wild-type host and in the host of lower affinity. These levels were increased in hosts bred to an IL-7 Tg background. Most injected cells of lower affinity and wild-type did not proliferate in any host, and recoveries from the heterologous hosts were lower than seen for the highest affinity cells. The authors conclude that the survival advantage of high affinity over low affinity cells is a result of increased competitiveness for specific self-MHC/peptide ligands and an enhanced responsiveness to IL-7.
Lymphopenia-induced CD8+ T cell proliferation
Naive CD8+ T cells can be activated by self-MHC/peptide complexes in mice rendered lymphopenic by irradiation or gene deletion. Newborn mice provide a natural lymphopenic environment to study the acquisition of a memory phenotype as a result of lymphopenia-induced proliferation (LIP). Schüler et al. (p. 15
) reconstituted neonatal C57BL6 (B6) mice with purified, CFSE-labeled CD8+ T cells from naive adult congenic mice. A total of 67%, 64%, and 41% of cells recovered from spleens of recipients injected 1 day, 4 days, and 7 days, respectively, after birth had proliferated (CFSElow) and had a memory (CD44high) phenotype. Nearly all cells recovered from similarly treated recombination-activating gene-deficient mice were also CFSElowCD44high, whereas most cells from injected B6 adult mice were CFSEhighCD44low. The majority of CD8+ T cells expressing a fluorescent protein maintained their CD44high phenotype at 8 wk after transfer. CFSE-labeled CD44lowCD8+ T cells transferred into B6 neonates proliferated and became CD44high. Pretreatment of B6 neonates with a mixture of mAbs against IL-7 and the IL-7R 
-chain prevented LIP above background values seen in adult B6 recipients. Both injected and endogenous CD8+ T cells recovered 2 wk later from spleens of neonates injected on day 1 produced IFN-
. The authors conclude that LIP-induced generation of memory CD8+ T cells in the neonate occurs before reconstitution of the naive T cell repertoire.
Inactivating bacterial virulence factors
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Clearing established HSV infection
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Antileukemic allogeneic NK cells
Allogeneic NK cells are used clinically to treat hematologic malignancies. Efforts are made to attain the "perfect mismatch" toachieve maximum NK cell-mediated lysis of the HLA-mismatched recipient leukemic cells. Leung et al. (p. 644 ) looked at the degree of mismatch between inhibitory killer-cell Ig-like receptors (KIR) on the donor’s NK cells and in the recipient’s HLA repertoire in stem cell transplants. This receptor-ligand model was most successful in predicting relapse of primary hematologic malignancies in 36 pediatric patients compared with a KIR ligand-ligand model and a NK cell cytotoxicity model. Recipient NK cells in 22 patients receiving purified CD34+ cells from an HLA-haploidentical donor assumed a donor specific KIR expression pattern within 3 mo of transplantation. NK cell-mediated lysis in vitro was highest against leukemia cells expressing the lowest numbers of transfected KIR HLA ligands. In vivo experiments in nonobese diabetic/SCID mice transplanted with the human NK cells and human leukemia cells showed that leukemia incidence was lowest in animals expressing the lowest numbers of transfected KIR HLA ligands. Prestimulation with both IL-12 and IL-18, or IL-12 alone, of leukemia cells expressing the highest number of KIR HLA ligands (the cells most resistant to NK-mediated lysis) rendered the cells sensitive to NK killing. The authors conclude that the best donor for NK transplantation would have the largest number of mismatch pairs but would have at least one KIR that recognizes an HLA on the recipient’s tumor cells.
IL-12 and Th1 differentiation
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may be an alternative route to Th1 differentiation of naive T cells has not been rigorously studied. Athie-Morales et al. (p. 61
) used an APC-free human in vitro Th1/Th2 differentiation model to determine the direct actions of IL-12 and IFN-. IFN- only doubled the proportion of IFN--producing cells, whereas IL-12 caused a nearly 5-fold increase compared with T cells activated without polarizing factors. However, only the IL-12-induced STAT4 activation was sustained (up to 48 h) and the constant presence of IL-12 was required. Cells pretreated with IFN- were refractory to further IFN- stimulation but could be stimulated by IL-12. Cell surface expression of one subunit of each cytokine receptor was down-regulated by 4 h after exposure to its ligand. IL-12 receptor subunit expression recovered by 24 h in the presence of IL-12; in contrast, IFN- receptor subunit expression did not recover in the presence of IFN-. IL-2 strongly increased the IL-12/STAT4 response through up-regulated expression of the IL-12 receptor subunit. The ability of IL-12 to activate T cells was lost in the presence of IL-2 Abs. Prolonged exposure (72 h) to IL-12 in the presence of IL-2 promoted optimal Th1 cell differentiation. IL-2 had no effect on the IFN-/STAT4 response. The data show the requirement for cytokine signals of long duration, as occurs with IL-12 but not with IFN-, in Th1 development. Summaries written by Dorothy L. Buchhagen, Ph.D.
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