Functional allelic exclusion

Most T cells express a single TCR at the cell surface. Once a functional TCR is expressed, suppression of further TCR recombination events mediates monoclonality of T cells. However, the identification of T cells bearing two different TCRs has shown such genetic allelic exclusion to be “leaky”. In the Proceedings of the National Academy of Science USA, Sant'Angelo et al. demonstrate an additional mechanism by which T cells maintain monoclonality. Despite transcribing all four mRNA species, T cells from double TCR-transgenic mice do not simultaneously express both available TCRs at the cell surface. Thus, cell surface expression of a second TCR may be blocked after translation. This process is likely controlled during the assembly of the αβ heterodimer.

Proc. Natl Acad. Sci. USA 98, 6824–6829 (2001)

A snug fit: CR2-C3d

Deposition of activated serum complement proteins on foreign surfaces links adaptive and innate humoral immune responses. The complement receptor CR2 amplifies signals received through the BCR and contributes to B cell tolerance. As reported in Science, Szakonyi et al. used X-ray structure determination to resolve the issue of how CR2 recognizes its ligand C3d, which covalently attaches to antigen. The CR2 binding interface formed by two membrane-proximal consensus repeats are fixed in space by hydrophobic interactions, which fold into V-shaped β barrels that have extensive shape complementarity with the binding surface of C3d. The structure explains previous observations for this receptor-ligand interaction and reveals potential therapeutic interaction sites.

Science 292, 1725–1728 (2001)

Avoiding graft-versus-host disease

Effective cancer immunotherapy strategies have been hampered by problems associated with bolstering patients' immune recognition of tumor-specific neo-self antigens and, when allogeneic bone marrow transplantation is used, development of graft-versus-host disease (GVHD). In Nature Medicine, Perreault and colleagues show effective elimination of malignant leukemic cells, without provoking GVHD, by adoptive transfer of primed T lymphocytes specific for a single immunodominant minor histocompatibility antigen (MiHA) into allogeneic recipients. Avoidance of GVHD required that no other minor host-reactive T cells were present at time of transplantation, as epitope spreading primes these cells against host tissues. The strategy of selective transfer of ex vivo–primed cytolytic T cells targeted to a single MiHA may lead to effective anti-cancer therapies in the clinic.

Nature Med. 7, 789–794 (2001)

Life in the marginal zone

Trapping of blood-borne particulate antigens by marginal zone (MZ) B cells is thought to bridge innate immune responses with the acquisition of long-term adaptive humoral immunity. Two reports in Immunity describe how MZ B cells arise and demonstrate the active role played by these cells in generating early antibody responses. Cariappa et al. show that signals received through the BCR act as a rheostat in recent bone marrow emigrants to develop into either MZ cells or follicular B cells. Thus, endogenous antigen interactions drive naïve B cell development in the periphery. Martin et al. show that MZ B cells become antibody-producing plasma cells within hours of antigen interaction, thus play a direct early role in clearing blood-borne pathogens.

Immunity 14, 603–615 (2001) and Immunity 14, 617–629 (2001)

Human regulatory T cells

Immunological self-tolerance is critical for the prevention of autoimmunity. In rodents, one mechanisms by which self-tolerance is maintained is via CD4+CD25+ regulatory T cells. In the Journal of Experimental Medicine, three groups—Levings et al., Dieckmann et al. and Jonuleit et al.—have isolated human regulatory CD4+CD25+ T cells and confirmed that these cells resemble their murine counterparts. For example, these cells express CTLA-4 and are hyporesponsive to stimulation with allogeneic dendritic cells. In addition, they can suppress CD25− T cell responses to anti-CD3 stimulation. They produce IL-10 and TGF-β, but these are not directly required for the suppressor activity. The identification of regulatory CD4+CD25+ T cells has important implications for therapy and study of tolerance in humans.

J. Exp. Med. 193, 1285–1294 (2001), J. Exp. Med. 193, 1295–1302 (2001) and J. Exp. Med. 193 , 1303–1310 (2001)

Two opposites attract

Chemokine receptors undergo ligand-mediated homodimerization to trigger Ca2+ flux and chemotaxis. In EMBO Journal, Martinez-A. and colleagues show that the chemokine receptors CCR2 and CCR5 can also heterodimerize. Simultaneous stimulation with CCL2 and CCL5 induces heterodimerization of CCR2-CCR5 and triggers a Ca2+ response at lower ligand concentrations than either chemokine alone. Although this process recruits both receptor-associated signaling complexes, the heterodimer activates another signaling pathway involving Gq/11. This delays activation of PI3K, causes a pertussis toxin–resistant Ca2+ flux and triggers cell adhesion instead of chemotaxis. This may explain chemokine signaling desensitization and regulation of cell migration during immune and inflammatory responses.

EMBO J. 20, 2497–2507 (2001)

Pten in T cell homeostasis

The tumor suppressor gene Pten encodes a multifunctional phosphatase that dampens proliferation and survival signals generated through phosphatidyl inositol-3,4,5-triphosphate. Pten−/− mice are nonviable, whereas mice heterozygous for Pten expression often develop lymphoid malignancies and autoimmune disorders. In Immunity, Suzuki et al. generate T cell lineage–specific Pten−/− mice that display multiple defects in T cell tolerance and homeostasis. Mutant mice have increased CD4+ cells in the periphery, develop CD4+ T cell lymphomas and have increased autoantibody production. Pten−/− T cells hyperproliferate, secrete more TH1 and TH2 cytokines and resist apoptosis. Pten−/− T cells show increased PKB (Akt) and Erk phosphorylation in response to T cell receptor stimulation. Thus, Pten is an important regulator of T cell tolerance and homeostasis.

Immunity 14, 523–534 (2001)