Immunology highlights from the recent literature

Damaging DNA

RAG-1 and RAG-2 proteins introduce double strand breaks (DSB) in the genes encoding immunoglobulins and TCRs. This cleavage generates four free-end intermediates that require ubiquitously expressed factors that function in general DSB repair. It was thought that broken intermediates during V(D)J recombination are sequestered from the DNA damage surveillance machinery, however, this does not appear to be the case. In Science, Nussenzweig and colleagues show that the Nijmegen breakage syndrome protein (NSB1) and histone γ-H2AX, which associate with irradiation-induced DSBs, are also found at sites of V(D)J recombination-induced DSBs in developing thymocytes. The results suggest that surveillance of TCR recombination intermediates by NSB1 and γ-H2AX may be important for preventing oncogenic translocations.

Science 290, 1962–1964 (2000)

Speaking semaphore

Semaphorins are proteins that carry “sema” domains in their NH₂-termini and they play a role in neuronal guidance. In Immunity , Kikutani and colleagues identified CD72, expressed throughout B cell differentiation, as a semaphorin. This molecule is a functional receptor for CD100 and stimulation via this ligand turns off the negative signaling effects of CD72. The group went on to generate and characterize CD100 gene-targeted mice. The mutant mice appear developmentally normal even though there is broad expression of CD100 receptors. However, there was severe impairment of B1 cell development and immune responses, demonstrating that CD100-CD72 interactions are essential to the immune system.

Immunity 13, 621–631 (2000) & Immunity 13, 633–642 (2000)

New cytokine, IL-23

In Immunity, Kastelstein and colleagues describe a helical cytokine, identified by searching sequence databases with an IL-6 subfamily structure. The protein, p19, shows no biological activity alone. However, in combination with the p40 subunit of IL-12, p19 forms a biologically active cytokine, referred to as IL-23. The p19p40 complex is naturally expressed by activated mouse and human dendritic cells and has biological activities that partially overlap with IL-12. The cytokine IL-23 binds to IL-12Rβ1 but not IL-12Rβ2, however it does activate STAT4 in stimulated T cell blasts. As with IL-12, human IL-23 stimulates IFN-γ production and proliferation in stimulated T cell blasts. A unique role of IL-23 is in inducing strong proliferation of memory cells.

Immunity 13, 715–725 (2000)

Mobile cells

Inflammatory stimuli induce dendritic cell (DC) maturation and chemokine receptor CCR7 expression. The ligands CCL19 and CCL21 are chemotactic for CCR7. CCL21 appears to mediate DC and T cell trafficking to the lymph nodes but the role of CCL19 is unclear. In Cell, Robbiani et al. show that leukotriene C₄ (LTC₄) transporter multidrug resistance-associated protein 1 (MRP1) is involved in DC migration. In MRP1^−/− mice, DC migration from the epidermis to the lymph nodes is reduced but can be restored using exogenous cysteinyl leukotrienes LTC₄ or LTD₄. These leukotrienes promoted chemotaxis to CCL19 in vitro and antagonism of CCL19 inhibited DC migration out of the epidermis in vivo. Thus, MRP1 regulates CCL19-dependent mobilization of DC to lymph nodes.

Cell 103, 757–768 (2000)

Lipid raft–independent signaling

Signaling via the BCR results in activation of mature B cells and apoptosis, receptor editing or anergy in immature B cells. The BCR is rapidly translocated into lipid rafts after antigen-induced BCR activation in mature B cells. The lipid rafts concentrate proteins including the Src family kinase Lyn. After cross-linking, the BCR and Lyn are phosphorylated and the BCR is rapidly internalized. In the Journal of Immunology, Sproul et al . show that, in immature B cells, the BCR does not translocate into lipid rafts or get internalized after receptor cross-linking. The immature BCR initiates signaling from outside the lipid rafts as shown by the induction of phosphoproteins and subsequent apoptosis. This may explain the different outcomes following signaling in immature and mature B cells.

J. Immunol. 165, 6020–6023 (2000)

Sads aid death

Fas–Fas ligand interaction can induce apoptosis. FADD, an apoptotic-inducing adapter protein binds to Fas and to pro-caspase-8. Formation of this Fas-death inducing signaling complex or Fas-DISC is the first event that occurs in Fas-mediated apoptosis. In Nature Medicine, Suzuki et al. have identified another component of the Fas-DISC called Sads. During Fas-mediated cell death, Sads enhance the association of FADD and pro-caspase-8. Mutation studies showed Sads contain FADD- and caspase-8–interactive domains. Fas-mediated apoptosis was delayed in cells depleted of Sads. Interestingly, Sads mRNA was down-regulated in colon carcinoma cells, which are resistant to cell death, and transient expression of Sads increased the susceptibility of a colon carcinoma cell line to Fas-mediated cell death. Thus, Sads represents another cell death–associated factor that enhances Fas-DISC formation.

Nature Med. 7, 88–93 (2000)

Complementing viral infection

Hepatitis C virus (HCV) can persist in infected individuals despite the presence of anti-viral T cells. The HCV core protein is expressed during the early phase of HCV infection and can suppress anti-viral CTL responses in a murine model. In the Journal of Clinical Investigation, Kittlesen et al. have investigated the mechanism of HCV core-mediated immunosuppression in humans. They found that the core protein binds the gC1q receptor (gC1qR) to a region distinct from C1q, which is the natural ligand of gC1qR. Both C1q and core protein can inhibit T cell proliferative responses in vitro . Importantly, anti-gC1qR reversed the core-induced inhibition of T cell proliferation. The binding of core protein to gC1qR may therefore promote the establishment of persistent infection by suppressing the host immune response.

J. Clin. Invest. 106, 1239–1249 (2000)