Detrimental regulatory T cells

Maintenance of immunological homeostasis and the prevention of autoimmunity are dependent on the presence of normal numbers of CD4+ regulatory T cells. However, in the Proceedings of the National Academy of Science, Iwashiro et al. show expansion of CD4+ regulatory T cells in response to chronic retroviral infection can lead to immunosuppression. Mice chronically infected with Friend retrovirus had an overabundance of splenic CD4+ regulatory T cells and certain anti-tumor responses were lost. CD4+ T cells from chronically infected mice inhibited the generation of CTLs in vitro through a mechanism(s) involving TGF-β and CTLA-4. Adoptive transfer of CD4+ T cells from chronically infected mice induced immunosuppression in uninfected recipients. These results may explain why immunosuppression can occur before T cell depletion in HIV infection.

Proc. Natl Acad. Sci. USA 98, 9226–9230 (2001)

Inflammatory superantigen

Inflammatory bowel disease is associated with abnormal T cell responses to enteric bacteria. However, the identity of the relevant microbial antigen is unknown. In Immunity, Dalwadi et al. show that I2, a Crohn's disease-associated microbial gene, is present in the murine intestine. In unimmunized mice, I2 stimulates the proliferation of naïve CD4+ T cells and secretion of IL-10. The I2-specific CD4+ T cell response is dependent on MHC class II–mediated recognition but does not require antigen processing. All responding CD4+ T cells belong to the TCR Vβ5 subpopulation. These results indicate that I2 is a new class of superantigen and that the I2 microorganism may play a role in colitis pathogenesis in susceptible hosts.

Immunity 15, 149–158 (2001)

Potential Leishmania vaccine

Leishmania parasites are transmitted to their vertebrate hosts by infected phlebotomine sand fly bites. Components of sand fly saliva enhance Leishmania infection, whereas immunity to saliva may confer protection to subsequent infection. In the Journal of Experimental Medicine, Valenzuela et al. have characterized the main proteins in the salivary glands of the sand fly Phlebotomus papatasi that may serve as antigens. One protein called SP15 could protect vaccinated mice challenged with Leishmania plus salivary gland homogenates (SGH). A DNA vaccine of the salivary SP15 gene afforded the same protection. Immunization induced both antibody and delayed hypersensitivity (DTH) responses. However, B cell–deficient mice receiving the SP15 vaccine also controlled Leishmania infection when injected with the parasite plus SGH. Thus, the protective effect of this vaccine is due to the DTH response against salivary proteins.

J. Exp. Med. 194, 331–342 (2001)

Transcription without integration

Formation of integrated provirus into host chromatin is essential for HIV replication. However, integration is limited by the quiescent nature of most circulating T cells, which are nonsupportive of HIV replication. The barrier to integration can be overcome by increasing T cell activity. The early HIV gene products Nef and Tat can both increase T cell activity; however, the requirement of provirus formation for viral gene expression would seemingly preclude a role for these proteins in resting cells. In Science, Wu and Marsh show that HIV infection of resting cells leads to selective transcription of nef and tat before integration. Preintegration transcription of these genes increases T cell activation and viral replication.

Science 203, 1503–1505 (2001)

BiP release by light chains

Unfolded Ig heavy chains are retained in the endoplasmic reticulum by the chaperone protein BiP. Ig light chain synthesis promotes assembly of complete Ig molecules, which then can migrate to the cell surface. In Immunity, Hendershot and colleagues show how BiP is released from the Ig heavy chain. More importantly, they show how Ig heavy chain misfolding is prevented, which is critical given the diversity of Ig chains that can be expressed by B cells. BiP removal in vitro causes irreversible misfolding, due to aggregation of hydrophobic patches found within the CH1 domain. BiP interaction with Ig heavy chains is stable in vivo, unlike the cycling interactions of other chaperone proteins. Light chains trigger rapid ATP-dependent BiP release. Thus, by regulating BiP ATPase cycling, light chains control the availability of heavy chain partners.

Immunity 15, 105–114 (2001)

SIAH controls BOB

The B cell transcriptional coactivator BOB, also known as OBF-1 or OCA-B, interacts with octamer proteins via its POU domain to regulate gene transcription in peripheral B cells. Defects in germinal center formation occur in mice deficient for BOB. In the EMBO Journal, Boehm et al. and Tiedt et al. report BOB activity is regulated post-translationally by SIAH1 and SIAH2, mammal homologs of Drosophila protein seven in absentia. SIAH proteins are E3 ubiquitin ligases that target BOB for degradation in the proteosome. Although BOB is constitutively expressed, interactions between BOB and SIAH control the effective protein concentrations within B cells. Importantly, activation of B cells alters these interactions leading to an increase in BOB protein and thus effects changes in B cell transcriptional activity.

EMBO J. 20, 4143–4152 & 4153–4162 (2001)

Trans-costimulation in vivo

T cell activation requires both antigenic and costimulatory signals that are provided by APCs. Although third-party costimulation has been shown in vitro, the in vivo relevance of trans-costimulation in T cell activation has not been demonstrated. In the Journal of Immunology, Mandelbrot et al. show costimulation in trans is as effective in promoting allograft rejection as costimulation provided in cis. Donor hearts from CD80−CD86− mice were transplanted into recipients whose peripheral APCs lacked expression of MHC class II molecules but whose CD4+ T cells were functional (II−/4+ mice). Indirect antigen presentation is precluded in this transplantation model, hence any rejection observed must occur by trans-costimulation. These results will affect any development of therapeutic strategies to promote graft survival by preconditioning recipients with the use of costimulatory molecule blockade.

J. Immunol. 167, 1174–1178 (2001)