Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA
Molecules of microbial origin, and synthetic derivatives of these molecules, have long been used for their immuno-adjuvant effect, and as the key sensors of microbial infection, Toll-like receptors (TLRs) are thought to be essential for adjuvanticity. In compound homozygous mutant (DKO) mice that lack functional MyD88 and TRIF, there is complete abrogation of all TLR signaling. Such animals therefore comprise a unique model with which to study TLR-independent immune responses. Surprisingly, these mice are still able to generate strong adaptive immune responses. Subcutaneous administration of syngeneic murine cells expressing ovalbumin and rendered apoptotic by exposure to _-irradiation resulted in a robust CD8 T cell response in vivo. This response was depending on the recognition of apoptotic cells by lymphoid DCs leading to type I IFN production.
We have initiated a forward genetic approach using N-Ethyl-N-Nitrosourea to identify genes that are essential components of this pathway. Currently, we have identified a total 14 mutations that show a reduced or absent CD8+ T cell response after immunization with act-mOVA cells. These include the ENU germline mutations; 3d (Unc3b13d/3d), oblivious (Cd36obl/obl) and Jinx (Unc13djnx/jnx), all of which selectively abolish MHC class I and/or II responses.
We propose that this mode of adaptive immune activation evolved to permit the sensitive detection of intracellular microbial infections, particularly viral infections, which frequently induce apoptotic cell death, but may also be important in transplantation, autoimmunity, and vaccine development.