Immunology highlights from the recent literature

A SLAP in the right direction

During positive selection, TCR expression by double-positive (DP) thymocytes is down-regulated. In Immunity, Weiss and colleagues investigate the role of Src-like adapter protein (SLAP) in TCR down-regulation and thymocyte development. SLAP expression is developmentally regulated; expression is low in double-negative thymocytes, peaks in DP thymocytes and decreases again in more mature cells. SLAP deficiency leads to up-regulation of TCR and CD5 expression at the DP stage. Positive selection of SLAP-deficient thymocytes expressing the DO11.10 transgenic TCR is enhanced compared to that in wild-type mice. Furthermore, the complete lack of positive selection seen in ZAP-70^−/− mice is partially rescued by SLAP deletion. These results show that SLAP is important in thymocyte development by regulating TCR expression levels during positive selection.

Immunity 15, 457–466 (2001)

Eradicating tumors

Most tumors can evade the immune system despite the existence of tumor-specific antigens and tumor-specific T cells. A number of factors secreted by tumor cells, such as TGF-β, have been shown to mediate this process. In Nature Medicine, Gorelik and Flavell report testing the role of TGF-β in tumor immune evasion by using transgenic mice with T cells defective in TGF-β signaling. Mice with T cells insensitive to TGF-β signaling resist tumor challenge. Specific blockade of TGF-β enhances the generation of the anti-tumor immune response. Tumor eradication is associated with increased numbers and activity of tumor-specific CD8⁺ cytotoxic T lymphocytes. Thus, T cell-specific blockade of TGF-β signaling could be useful therapeutically to enhance T cell–mediated anti-tumor immunity.

Nature Med. 7, 1118–1122 (2001)

No nibbling at the TCR V_α

After a successful V_β rearrangement, the TCR V_α locus is thought to undergo multiple rounds of recombination to maximize the generation of αβ T cells. In the EMBO Journal, Malissen and colleagues report data that dispute this model of coordinated, polarized nibbling at the TCR α loci. They examined V_α-J_α rearrangements in a large panel of human and murine T cell clones. Although a loose correlation exists for the J_α segment used by both chromosomes, they found no such coordinated selection for V_α. Instead of the predicted use of the 3′-most V_α with the 5′-most J_α, there was a distribution of V_αJ_α rearrangements. In situ hybridization ruled out homologous pairing of the J_α loci as an explanation for the positional coincidence in their usage. Thus, J_α and V_α usage cannot be explained by DNA tracking or interallelic sensing but may be explained by a locus-wide accessibility model.

EMBO J. 20, 4717–4729 (2001)

Targeting NK tumor immunity

Natural killer cells are thought to play an important role in tumor surveillance, but whether tumor antigens could activate NK cells in vivo remained unknown. In Nature, Raulet and colleagues show that ectopic expression of either Rae1 or H-60, ligands for the NK receptor NKG2D, stimulates NK cytolytic reactivity to tumors bearing these ligands. Tumor rejection upon primary challenge is dependent upon NK or CD8⁺ cells, as depletion of either cell type or blocking of the interaction between NKG2D and its ligand result in increased tumor growth and metastasis. Moreover, activated NK cells prime T cells for subsequent challenge against ligand-negative tumors. Immunity is tumor-specific. Thus, NKG2D receptor engagement can evoke potent anti-tumor responses in vivo and promotes immunological memory against tumor cells.

Nature 413, 165–171 (2001)

Acetylation regulates NF-κB

Activation of NF-κB leads to expression of many genes associated with inflammatory immune responses. Much is known about control of NF-κB localization by IκB but very little about how active nuclear NF-κB is turned off. In Science, Chen et al. report the reversible acetylation of the RelA subunit of NF-κB, which controls its ability to reassociate with newly synthesized IκB. Acetylated forms of RelA, which arise from its association with the coactivators CBP/p300, interact only weakly with IκB, whereas deacetylated RelA is bound to IκB and shuttled out of the nucleus. RelA is deacetylated by specific interaction with histone deacetylase 3, which acts as a molecular switch to turn off active NF-κB. Thus, return to a latent NF-κB activation state is governed by RelA deacetylation.

Science 293, 1653–1657 (2001)

Peptide trimming by gp96

MHC class I molecules present peptides of a defined length of eight or nine amino acids, but how peptides of this precise size are generated remains obscure. In the Journal of Biological Chemistry, Srivastava and colleagues report that chaperone protein gp96 is an aminopeptidase. Gp96 is a major endoplasmic reticulum–resident protein that binds peptides transported into the ER lumen. Purified gp96 is able to trim 19-aa peptides derived from vesicular stomatitis virus to 8-aa peptides, which elicit cytolytic responses when presented by H-2^k molecules to specific CTLs, whereas the precursor peptides could not. The aminopeptidase and ATPase activities of gp96 are not shared by related chaperone proteins. This biochemical evidence suggests a crucial role for gp96 in peptide presentation.

J. Biol. Chem. 276, 33313–33318 (2001)

Controlling T_H2 differentiation

The Polycomb group of genes, such as mel-18, regulate not only homeobox gene expression but also the cell cycle of immature lymphocytes. In Immunity, Kimura et al. investigate the role played by Polycomb gene products in the regulation of T helper cell (T_H) differentiation. Mature peripheral T cells from Mel-18–deficient mice proliferated normally in response to TCR stimulation. However, production of T_H2 cytokines is significantly diminished, whereas IFN-γ secretion is modestly increased. T_H2 differentiation is impaired in Mel-18^−/− CD4⁺ T cells and is associated with decreased demethylation of the IL-4 gene locus and reduced GATA-3 induction. In addition, antigen-induced IgG1 production and Nippostrongylus brasiliensi–induced eosinophilia are impaired in vivo. Thus Polycomb gene products participate in regulating T_H2 differentiation and T_H2-dependent immune responses.

Immunity 15, 275–287 (2001)