Nature Methods

A simple strategy for creating mice that express multiple foreign proteins could help some scientists to study essential processes of immune development without the trouble of transgenics, as described in the March issue of Nature Methods.

Immature T-cells produce a variety of multi subunit T-cell receptors (TCRs), which exhibit enormous sequence variability. Proper maturation depends on the extent to which a T-cell’s TCRs can interact with host-specific major histocompatibility complex (MHC) proteins. If this interaction is too strong or too weak, maturation will not take place. Immunologists have typically studied this important process in vivo via TCR engineering, generating transgenic animals that exclusively produce T-cells expressing TCRs with specific subunit combinations.

Dario Vignali’s laboratory previously described a system that allows single DNA molecules to act as ‘assembly lines’ for the simultaneous production of multiple independent proteins. Here the team adapts this method to generate retroviral constructs expressing multiple TCR subunits, which were used to infect mouse marrow stem cells. These cells are transplanted into marrow-depleted recipients to make ‘retrogenic’ mice that produce only one type of TCR. This approach bypasses the time and trouble of generating and crossing multiple transgenic strains, and ensures equal production of all protein products—an essential consideration for TCR assembly.

In an associated ‘News and Views’ piece, Rémy Bosselut comments that although these retrogenics may not fully supplant transgenics for studying TCR-MHC interactions in vivo, they offer a rapid and elegant alternative for TCR mutant analysis or experimental scenarios in which standard transgenics are not an option.

CONTACT
Dario A. A. Vignali (St. Jude Children’s Research Hospital, Memphis, TN, USA)
Tel: +1 901 495 2332; Email: dario.vignali@stjude.org


Rémy Bosselut (National Cancer Insitute, Bethesda, MD, USA)
Tel: +1 301 402 4849; Email: remy@helix.nih.gov

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