Anthony Defranco, PhD

Department of Microbiology and Immunology
+1 415 476-5488
Research Overview: 

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



The Role of MAP Kinases, Phosphatidylinositol 3-Kinase, and Ceramide in LPS-induced Signaling in Macrophages.

Anthony L DeFranco, Alexander J Finn, Julie Hambleton, Mary T Crowley, Mary Lee MacKichan, Steven L Weinstein

Use of prasugrel vs clopidogrel and outcomes in patients with and without diabetes mellitus presenting with acute coronary syndrome undergoing percutaneous coronary intervention.

International journal of cardiology

Faggioni M, Baber U, Chandrasekhar J, Sartori S, Claessen BE, Rao SV, Vogel B, Effron MB, Poddar K, Farhan S, Kini A, Weintraub W, Toma C, Sorrentino S, Weiss S, Snyder C, Muhlestein JB, Kapadia S, Keller S, Strauss C, Aquino M, Baker B, Defranco A, Pocock S, Henry T, Mehran R

B Cell-Intrinsic MyD88 Signaling Promotes Initial Cell Proliferation and Differentiation To Enhance the Germinal Center Response to a Virus-like Particle.

Journal of immunology (Baltimore, Md. : 1950)

Tian M, Hua Z, Hong S, Zhang Z, Liu C, Lin L, Chen J, Zhang W, Zhou X, Zhang F, DeFranco AL, Hou B