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Therapeutic TNF
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B and JNK and in cytotoxicity assays. Introduction of the dipeptide linkers during scTNF creation did not induce formation of higher aggregates, nor did it affect TNFR-specific interaction sites on the molecule. scTNF was found to be much more stable than wild-type TNF both in vitro and in vivo, yet had much lower liver toxicity than wild-type TNF. Finally, the authors compared the antitumoral activity of scTNF vs wild-type TNF and found that their new reagent was as effective as wild type or more effective, depending on the tumor model that was used. The development of scTNF thus introduces a new strategy for TNF-based therapeutics. Memories of HIV
A loss of memory T cell responses is known to be associated with HIV disease progression. Ladell et al. (p. 7907
) studied patients who ingested deuterated water to analyze the in vivo lifespan and phenotype of long-lived memory CD8+ T cells in HIV-infected and uninfected individuals. Analysis of CD8+ T cell subpopulations showed that naive T cells and central memory T cells (TCM) decreased with declining CD4+ T cell counts in HIV-infected individuals, whereas the RA effector memory T cell subset (TEMRA) was expanded in HIV-infected individuals compared with controls. The TCM subset was found to have a significantly shorter lifespan in HIV-infected individuals with a high viral load than in uninfected individuals, and this population lost expression of IL-7R
in more advanced disease. In contrast, the TEMRA population demonstrated a long half-life in HIV-infected individuals, accumulated as disease progressed, and lost expression of CD57. These data validate the use of the stable isotope/FACS/MS method to measure the kinetics of low-abundance human T cell populations in vivo. In addition, the data support the idea that TCM cells are the "true" memory CD8+ T cells important for protection against HIV progression and that the observed loss of these cells may be responsible for the loss of T cell memory activity in infected individuals.
Which Cells Cause EAE?
The recent discovery of an important role for Th17 cells in the induction of experimental autoimmune encephalomyelitis (EAE) has led some to question the long-held belief that Th1 cells mediate this disease. Lees et al. (p. 8066
) hypothesized that a small population of contaminating IL-17-producing cells in an adoptively transferred Th1 cell line would preferentially and quickly accumulate in the CNS following transfer. To test this hypothesis, the authors monitored the phenotype of T cells invading the CNS at different time points following adoptive transfer of a myelin oligodendrocyte glycoprotein (MOG)-specific, Th1-polarized cell line. Unexpectedly, IL-17-producing adoptively transferred cells were not found to preferentially accumulate in the CNS during the initiation, peak, or resolution phases of acute EAE. However, IL-17-producing host cells were recruited to the CNS early and were maintained throughout disease. These cells were heterogeneous, consisting of both 
and β TCR+ T cells that were CD3+CD45+ and either CD4+CD8– or CD4+CD8+. Adoptive transfer of Th1 cells into IL-17–/– hosts resulted in amelioration of EAE, indicating that host production of IL-17 participates in disease pathogenesis. These data begin to clarify the relative roles of Th1 and Th17 cells in CNS autoimmunity.
Proliferative Synergy
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Dragging CD4 Down
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Contradictory 2B4
The CD2 family member 2B4, which is expressed on NK cells, T cells, and memory CD8+ T cells, has been shown to both activate and inhibit NK cell functions in mice. The mechanism by which this single receptor mediates opposing functions is unclear, and it has not been established whether human 2B4 can also mediate inhibitory functions. Chlewicki et al. (p. 8159
) therefore made a panel of 2B4-transfected cells to assess 2B4 activity in a controlled manner. Clones expressing human 2B4 or either of the two mouse 2B4 alleles could similarly mediate either activating or inhibitory functions. This activity generally correlated with 2B4 expression levels, such that lower surface expression favored activation and higher expression favored inhibition. The choice between activation and inhibition was also dependent upon the extent of 2B4 engagement; lower levels of cross-linking favored activation and higher levels favored inhibition. A third factor contributing to 2B4 function was expression of the adaptor molecule SLAM-associated protein (SAP); increasing levels of SAP favored activation over inhibition. In contrast, the adaptor molecules EAT-2A and EAT-2B did not appear to be required for inhibition. This clarification of 2B4 activity and its relation to three interrelated factors may have important implications for the understanding of NK cell activity and of multifunctional receptors in general.
Flexible Memory
Central memory CD4+ T cells (TCM) can protect against rechallenge with Leishmania major, and maintenance of immunity to this parasite requires the presence of IL-12. Pakpour et al. (p. 8299
) analyzed the plasticity of L. major-specific CD4+ TCM to determine whether these TCM are predetermined to become Th1 effector cells. First, the authors determined that in vivo-generated Th1 cells and effector memory CD4+ T cells did not require IL-12 to produce IFN-. However, although either in vitro- or in vivo-generated CD63Lhigh TCM proliferated in the absence of IL-12, these cells could only become IFN- producers in the presence of IL-12. This suggested that these L. major-specific TCM were not committed to the Th1 lineage, an idea that was supported by the observation that very few of these cells expressed T-bet. Interestingly, TCM cells adoptively transferred into IL-12-deficient mice could become IL-4 producers, indicating that these cells had the potential to differentiate into either Th1 or Th2 effectors. These data suggest that L. major-specific TCM do not differentiate from effector Th1 cells and therefore require additional signals to fully differentiate into effector cells.
Signaling Selection
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-chain connecting peptide motif (-CPM) on CD8 binding, T cell activation, and thymocyte differentiation. Transgenic mice bearing an -CPM-deficient TCR showed a severe defect in thymic positive selection. This defect could be linked to a change in the CD8:MHC interaction that led to a reduced affinity of -CPM mutant thymocytes for pMHC. The authors next analyzed the effect of -CPM deficiency on TCR signaling and found that -CPM mutant T cell hybridomas showed reduced TCR internalization compared with wild type and failed to produce IL-2 in response to either low- or high-affinity ligands. FRET and Western blot analysis then demonstrated that an intact -CPM domain was required for CD3
:CD8β interaction and subsequent CD3 phosphorylation in response to low-affinity ligands, explaining the positive selection defect observed in mice lacking -CPM. These data indicate the important role of -CPM in TCR signaling, both in T cell activation and thymic selection. Summaries written by Jennifer Hartt Meyers, Ph.D.
Related articles in The JI:
-Chain Connecting Peptide Motif Promotes Close Approximation of the CD8 Coreceptor Allowing Efficient Signal Initiation
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