Anthony Defranco, PhD

Professor
Department of Microbiology and Immunology
+1 415 476-5488

The DeFranco lab studies signal transduction by the B cell antigen receptor (BCR) and by Toll-like receptors (TLRs) and is particularly interested in how signaling supports the proper functioning of the immune system.  They are also interested in how alterations in these signaling pathways may lead to disease.

BCR signaling involves activation of intracellular protein tyrosine kinases of three types and downstream activation of a variety of signaling reactions.  Although Src-family tyrosine kinases play a very important role in the initiation of signaling, B cells express three family members and one of these, Lyn, also is important for feedback inhibition of BCR signaling.  In the absence of Lyn, BCR signaling proceeds with a slight delay, but feedback inhibition is defective, resulting in exaggerated signaling and spontaneous autoimmune disease that resembles the human disease systemic lupus erythrematosus.  A major project in the lab involves studying how deficiency in Lyn leads to defects in B cell tolerance and spontaneous autoimmune disease.  These studies are part of a long-term collaboration with Clifford Lowell, who studies the function of Lyn in myeloid cells and how alterations in myeloid cells also contribute to the autoimmunity observed in the Lyn-/- mice.  A second major project in this area is to understand how BCR signaling is differentially regulated between immature and mature B cells.  Immature B cells are highly sensitive to antigen, leading to tolerance-related responses such as receptor editing and anergy, whereas mature B cells are less sensitive but exhibit robust signaling when the BCR is strongly engaged, a dose response behavior which likely reflects a threshold for activation.  One of the feedback inhibitory pathways controlled by Lyn (involving CD22) is strongly active in mature B cells and less active in immature B cells, but this does not account for all differences in the sensitivity to antigen.  Recently we have begun to analyze how the diacylglycerol kinases may contribute to regulation of the activation of mature B cells.

TLR signaling is important for many immune responses and occurs in most if not all immune cell types in response to infections.  For this reason, it has been hard to distinguish the relative contributions of different cell types for TLR-dependent immune reactions.  To address this problem, we have created a conditional allele of the critical TLR signaling component Myd88 in which an essential exon is surrounded by loxP sites.  Cell type-specific expression of the Cre recombinase results in deletion of the Myd88 gene in that cell type.  We have used mice in which Myd88 is deleted to demonstrate that TLR signaling in dendritic cells plays an essential role for the innate immune restriction of growth by the single-celled parasite Toxoplasma gondii.  Similarly, Myd88 in dendritic cells was required for a normal magnitude IgG response to soluble protein antigens covalently coupled to a TLR ligand.  In contrast, Myd88 function in B cells, but not dendritic cells was found to greatly enhance the IgG germinal center response to virus particles.  This may represent an adaptation of the immune system designed to boost antibody responses to virus particles. These studies illustrate that TLR signaling is important for many immune responses and begin to define how this occurs in vivo.

Primary Thematic Area: 
Immunology
Secondary Thematic Area: 
Cancer Biology & Cell Signaling
Research Summary: 
Regulation of B Lymphocyte and Macrophage Function by Cell Surface Receptors

Websites

Publications: 

Determinants of Divergent Adaptive Immune Responses after Airway Sensitization with Ligands of Toll-Like Receptor 5 or Toll-Like Receptor 9.

PloS one

Lee LM, Ji M, Sinha M, Dong MB, Ren X, Wang Y, Lowell CA, Ghosh S, Locksley RM, DeFranco AL

Germinal centers and autoimmune disease in humans and mice.

Immunology and cell biology

DeFranco AL

LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity.

The Journal of clinical investigation

Proekt I, Miller CN, Jeanne M, Fasano KJ, Moon JJ, Lowell CA, Gould DB, Anderson MS, DeFranco AL

MyD88 Shapes Vaccine Immunity by Extrinsically Regulating Survival of CD4+ T Cells during the Contraction Phase.

PLoS pathogens

Wang H, Li M, Hung CY, Sinha M, Lee LM, Wiesner DL, LeBert V, Lerksuthirat T, Galles K, Suresh M, DeFranco AL, Lowell CA, Klein BS, Wüthrich M