The RIP-LCMV mouse model was created to break tolerance to a defined target autoantigen expressed by b-cells through a viral infection. Such a target antigen represents a component of ‘self’ and therefore the host is ignorant or tolerant to that antigen. Initiation of autoimmunity by virus-infection is twofold: First, the infection causes an activation of the innate immune system resulting in an inflammatory response involving the release of chemokines and cytokines. Those inflammatory factors in turn attract and activate leukocytes to the site of infection in a non-specific manner. Second, the presence of an identical antigen on both the b-cells and the infecting virus focuses this non-specific innate immune response specifically on the target antigen and thus breaks self-tolerance. Hence, after elimination of the intruding virus, the awakened immune response concentrates on the remaining transgenic target antigen expressed by the b-cells resulting in T1D. This scenario was experimentally reconstructed in the labs of Michael Oldstone (Scripps, La Jolla, CA) (Oldstone et al. (1991) Cell 65: 319-331) and Rolf Zinkernagel (Zurich, Switzerland) (Ohashi et al (1991) Cell 65: 305-317) in the early 1990’s. By using the rat insulin promoter (RIP) they created transgenic mice whose pancreatic b-cells expressed either the nucleoprotein (NP) or the glycoprotein (GP) of LCMV as defined target antigens. Expression of either target antigen per se does not lead to b-cell dysfunction, islet cell infiltration, hyperglycemia, or spontaneous activation of autoreactive lymphocytes. However, infection with LCMV results in T1D in >95% of RIP-LCMV mice.  

Induction of type 1 diabetes in the RIP-LCMV mouse model

(1) Transgenic RIP-LCMV mice expressing the glycoprotein (GP) or nucleoprotein (NP) of the lymphocytic choriomeningitis virus (LCMV) as self-components in their pancreatic b-cells are tolerant or ignorant to the (self)-transgene and thus neither destroy the b-cells nor develop T1D. (2) Induction of T1D in such mice is initiated by virus (LCMV)-induced inflammation of the pancreas that attracts and activates leukocytes to the site of virus infection. This process is mediated by predetermined programs of the innate immune system in response to LCMV-infection. (3) Once arrived at the target site LCMV-specific precursor lymphocytes expand and rapidly eliminate the virus. (4) After virus elimination activated LCMV-specific lymphocytes attack the only remaining target antigen, namely the LCMV-antigen transgenically expressed by the b-cells. This results in destruction of most of the b-cells, impaired insulin production and subsequently overt diabetes.

Just as proposed for human T1D, the onset of diabetes in RIP-LCMV mice depends on the action of both, autoreactive CD4 and CD8 T-cells and correlates with the numbers of auto-aggressive lymphocytes generated. In accordance, the incidence of disease varied between the individual transgenic lines ranging from 2 weeks (RIP-GP lines) to 1-6 months (RIP-NP lines). Further studies revealed the mechanism involved in the rapid compared to the slow onset diabetes: Transgenic lines expressing the LCMV-GP transgene exclusively in the b-cells of the islets manifested rapid-onset T1D (10-14 days after viral challenge). In these lines the high systemic numbers of auto-aggressive CD8 T-cells were sufficient to induce diabetes and did not require help from CD4 cells. In contrast, in lines expressing the LCMV-NP transgene in both the b-cells and in the thymus, T1D took longer to occur after subsequent LCMV challenge. Several lines of evidence indicated that in RIP-NP mice the anti-self (viral) CTL were of lower affinity and that CD4 T-cells were essential to generate anti-self (viral) CD8 lymphocyte-mediated T1D. In addition, mouse models in which transgene-encoded ‘target-antigens’ are expressed in the pancreatic b-cells, such as the RIP-LCMV and the INS-HA mouse, have demonstrated that the presence of autoaggressive T-cells alone is not enough to cause disease. Unspecific ‘bystander factors’, such as cytokines and chemokines generated during the acute inflammation after LCMV infection, are important to drive the autoaggressive response (b-cell destruction) in ‘antigen-specific’ models for T1D.

Immunopathogenic events following LCMV-infection in the RIP-LCMV model

LCMV-infection of the pancreas causes the release of ‘pro-inflammatory’ cytokines, such as TNFa, by resident macrophages. In turn, chemokines are released by activated endothelial cells as well as b-cells. Among them CXCL10 is the earliest chemokine to be expressed leading to high local concentrations at a very early time after LCMV-infection. CXCL10 predominantly attracts activated T-cells of the more aggressive Th-1 phenotype, which migrate into the inflamed tissue. Infiltrating LCMV-specific T-cells start destroying some b-cells in a perforin dependent manner. At a later stage further presentation of LCMV- and other islet antigens by professional antigen presenting cells, such as dendritic cells (DCs) leads to further proliferation and expansion of the autoaggressive T-cell repertoire. Islet antigen-specific, aggressive T-cells together with unspecific bystander factors destroy most of the remaining b-cells resulting in overt diabetes.


The RIP-LCMV model has become a very useful tool to study the etiology and the mechanisms of human autoimmune diabetes and to evaluate possible treatments, such as blockade of specific inflammatory factors, oral tolerance induction or DNA-vaccination. Besides having a clearly defined initiation point (LCMV-infection), the advantage of the RIP-LCMV system over other established models for T1D, such as the NOD mouse, is the presence of extensively characterized target antigens (GP, NP). The immune response against these target antigens can be visualized using flow cytometry by stimulation of splenocytes with LCMV-peptides or direct staining of CD8 T-cells with MHC class I-peptide tetramers. In addition, we recently demonstrated tracking of LCMV-specific CD8 T-cells by in situ MHC class I-peptide staining of quick-frozen tissue sections (McGavern et al (2002) Nat. Immunol. 10: 918-925).