V o l . 2 1 N o . 3 1 0 9

M A R C H 2 0 0 0

U P D A T EI M M U N O L O G Y TO D AY

Current literature

Antigen presentation to T cells is a centralfacet of the adaptive immune response.Major histocompatibility complex (MHC)class I molecules bind peptides in the endo-plasmic reticulum and present peptides derived from endogenous proteins, such asviral proteins. By contrast, MHC class IImolecules bind to peptides derived from exogenous proteins in the late endosomalcompartments. CD1 molecules are a familyof b2-microglobulin-associated non-poly-morphic glycoproteins that, in contrast toMHC class I and II molecules, have beenshown to present lipid and glycolipid antigens, and GPI-linked proteins.

Unlike other CD1 molecules, CD1a lacksthe specific cytoplasmic tail motif that isknown to induce localization of CD1 molecules to the endosomal compartment.In this study, Sugita and colleagues testedthe hypothesis that CD1a might represent aprocessing pathway distinct from the other

CD1 and MHC molecules. Using immuno-fluorescence microscopy and electron mi-croscopy as well as functional studies, theywere able to demonstrate functional andanatomical separation of the CD1a andCD1b processing pathways. Like MHC classII, CD1b molecules localize to late endo-somal compartments and require vesicularacidification for function. By contrast, CD1amolecules were found to localize to the recycling compartments of the early endo-somal pathway, and do not require acidifi-cation for function. Sugita and colleaguesspeculate that differential trafficking of theCD1 isoforms allows CD1 molecules to effi-ciently sample antigen from a variety ofcompartments, and detect microbes that mayattempt to evade the immune response byavoiding localization in specific compart-ments, such as mycobacteria.

Elaine Bell

Murine embryonic survival dependson regulation of complementXu, C. et al. (2000) A critical role for murinecomplement regulator Crry in fetomaternaltolerance. Science 287, 498-501

Activation of the complement system is afeature of both the innate and adaptive armsof the immune response. As a component ofnatural immunity, complement activationleads to enhanced phagocytosis, clearance of immune complexes, chemotaxis of in-flammatory cells and cell lysis. Althoughcomplement can bind to self tissues, cells areprotected because they express proteins thatinactivate complement. In humans, decayaccelerating factor (DAF) and membrane cofactor protein (MCP) are involved in inac-tivation of complement components. In ro-dents, a third protein, Crry, is also involvedin complement regulation.

In this study, Xu and colleagues set out togenerate Crry-knockout mice to investigatein vivo the role of Crry in protecting againstcomplement attack. However, no liveCrry2/2 mice were recovered, indicatingthat Crry plays a crucial role in pregnancy.Crry2/2 embryos died at day 10 after con-ception. Complement deposition was de-tected in both the embryo and placenta, aswell as infiltration of inflammatory cells.Crossing the Crry1/2 mice with C32/2 mice(in which complement is inactive) produced27% of pups that were Crry2/2, indicatingthat complement activation was the cause ofthe embryonic lethality of the Crry2/2 mice.

Although mice possess DAF and MCP aswell as Crry, neither DAF nor MCP are expressed in early embryos, leaving Crry asthe crucial regulator of complement activa-tion at this stage of murine development.Crry does not exist in humans, but DAF andMCP are both expressed in human placen-tas. Xu and colleagues propose that DAFand MCP play a similar role to Crry in con-trolling complement- mediated inflammationand tissue damage in early human pregnancy.

Elaine Bell

Distinct antigen processing pathway for CD1b moleculesSugita, M. et al. (1999) Separate pathways for antigen presentation by CD1 molecules. Immunity11, 743–752

Absence of T-cell receptor (TCR) interactionswith MHC molecules during developmentresults in peripheral T-cell pools, with agreatly reduced half-life. What happens if T cells develop in the presence of TCR–MHCinteractions but are then subsequently de-prived of access to MHC molecules in theperiphery? Here, Witherden and colleagueshave constructed MHC-deficient mice,engineered to express MHC class II only inthymic epithelial cells (TECs) in a tetracycline (tet)-controllable manner. The periph-ery of these animals is class II-negative. Insuch animals, class II expression in TECs canbe turned ‘on’ or ‘off’ simply by adminis-tration of the tet antibiotic in drinking water.

CD41 T cells develop normally in theMHC class II1 thymus and are exported tothe periphery where the half-life was a verymodest 3–4 weeks. This indicates that con-tinued TCR–MHC interactions are necessary

for survival of naive T cells, even in the ab-sence of antigen stimulation. TCR-mediatedsignalling in such ‘marooned’ T cells isclearly affected, with abnormally low levelsof CD3z phosphorylation and ZAP-70 re-cruitment to the TCR complex. HoweverCa21 fluxes in response to TCR crosslinkingare normal, suggesting that these cells arenot functionally inert.

These data confirm that the dependenceon TCR–MHC interactions of developingCD41 thymocytes clearly extends to naivemature CD41 T cells in the periphery. More-over, the absence of continued TCR–MHCinteractions purturbs the TCR signalling capacity of such naive cells. This emphasison antigen-independent TCR stimulationfor T-cell survival raises important questionsabout the MHC-positive ‘networks’ thatsupport the peripheral T-cell pool.

Rob Brines

Marooned T cells and TCR–MHC interactionsWitherden, D. et al.(2000) Tetracycline-controllable selection of CD41 T cells: half-life and survival signals in the absence of major histocompatibility complex class II Molecules J. Exp. Med.191, 355–364

Current LiteratureAre you interested in joining a literature

review panel for Immunology Today?If so please contact our Editorial Office at:

IT@current-trends.com