Projects


Role of T cell-NF-κB in transplantation and autoimmunity

NF-κB is a transcription factor that plays many essential roles in immune responses in vivo, from contributing to the formation of lymph nodes and Peyer’s patches to allowing generation and maturation of dendritic cells and controlling development and function of several T cell subsets.  Several immunosuppressive drugs, as well as many more in development, inhibit NF-κB as part of their mechanism of action.  However, NF-κB is a ubiquitous transcription factor the inhibition of which can cause many severe side effects in different organ systems.  Our laboratory has shown that T cell-restricted inhibition of NF-κB, using transgenic mice that express an NF-κB super-repressor selectively in T cells (IκBαΔN-Tg mice), results in permanent acceptance of fully allogeneic cardiac allografts and development of donor-specific tolerance via apoptosis of alloreactive T cells.  In these mice, T cell-NF-κB activity is inhibited downstream of several receptors, including the TCR, Toll-like receptors (TLRs) and tumor necrosis factor receptor (TNFR) family members.  To determine whether selective inhibition of TCR-NF-κB is sufficient for preventing allograft rejection, we have obtained CARMA1-KO mice that lack an adaptor molecule required for selectively linking the TCR and BCR to NF-κB.  CARMA1-KO mice also permanently accept fully allogeneic cardiac allografts, positioning the CARMA1-NF-κB axis as a very promising therapeutic target for clinical transplantation.  Importantly, mice deficient in CARMA1 are an invaluable tool to understand the consequences of inhibition of this pathway on the development and differentiation of T cell subsets.  We anticipate that drugs that would target NF-κB selectively in T cells rather than in all cell types may have fewer side effects than current immunosuppressive therapies while having the potential to induce transplantation tolerance or prevent/treat autoimmunity.  Our current results indicate that targeting CARMA1 abolishes the thymic development of natural regulatory T cells (nTregs).  Conversely, lack of CARMA1 promotes the differentiation of induced regulatory T cells (iTregs), underscoring CARMA1 as playing opposite functions in the generation of nTregs versus iTregs.  We are currently investigating the role of CARMA1 in the differentiation of Th17 cells as iTregs and Th17 differentiation is often reciprocally regulated.      We aim to define the precise role of CARMA1 and TCR-driven NF-κB in the development/differentiation of T cell subsets in vitro and in transplantation models in vivo


Therapeutic harnessing of T cell-NF-kB for anti-tumor therapy

T cells are essential for the immune-mediated elimination of tumors. However, tumor-specific T cells can be identified in cancer-bearing patients despite tumor progression, suggesting that tumor-reactive T cells may have impaired or suppressed effector functions. Importantly, tumor progression has also been associated with reduced activity of the transcription factor NF-κB in T cells. Together, these observations suggest that restoring activation of NF-κB in T cells of cancer patients may re-establish T cell-dependent tumor rejection. In collaboration with Tom Gajewski, our laboratory is studying whether constitutive activation of the transcription factor NF-κB selectively in peripheral T cells can indeed facilitate tumor rejection and if so by what mechanism. We hypothesize that constitutive activation of NF-κB in T cells should increase T cell survival, facilitate Th1 and Th17 differentiation, and prevent generation of induced regulatory T cells (iTregs), thereby enhancing the ability of T cells to reject tumors. This hypothesis is based on our results demonstrating that T cells with impaired NF-κB activity have defects in Th1 and Th17 differentiation, reduced cell survival, and increased conversion into iTregs. Thus, we postulate that constitutive activation of NF-κB in T cells should have the converse effects. Therapeutic strategies aimed at promoting T cell survival and amplifying T cell differentiation/effector function would be extremely desirable as novel cancer therapies.


Consequences of microbial signals on immune responses

One major goal in transplantation and autoimmunity is to develop new immunosuppressive agents with the potential to induce antigen-specific tolerance and thus avoid increased risk of infection and cancer in treated patients.  Considerable effort has been spent on the study of costimulation-targeting therapies, as these regimens successfully induce permanent acceptance of transplanted organs such as heart grafts and pancreatic islets in rodents.  However, in collaboration with Anita Chong, we have recently shown that infections at the time of transplantation potently antagonize the ability of costimulation-blockade therapies to achieve donor-specific tolerance.  Microorganisms contain molecular patterns that are recognized by toll-like receptors (TLRs) expressed on host and donor cells.  Our results indicate that engagement of a single TLR at the time of cardiac transplantation is sufficient to prevent graft acceptance induced by anti-CD154+/- donor-specific transfusion (DST) or CTLA-4-Ig in mice.  Understanding the mechanisms by which TLR signaling opposes pathways of transplantation tolerance is essential to develop novel therapies likely to be successful in the clinic, in patients constantly exposed to both commensal and pathogenic microorganisms.  These studies aim to understand the consequences of TLR signaling in vivo and should yield a deeper understanding of different facets of the interplay between innate and adaptive immune responses that may negatively impact establishment of tolerance in settings of transplantation and autoimmunity.   


Immune responses to Staphylococcus aureus in patients

In collaboration with Robert Daum and Anita Chong, we are conducting studies utilizing blood from patients enrolled in a randomized, double-blind trial of clindamycin, trimethoprim-sulfamethoxazole, or placebo for uncomplicated skin and soft tissue infections caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).  Our studies address the underlying cause for increased susceptibility to skin infections in the general population. In the last decade the incidence and frequency of MRSA infections has increased exponentially, particularly among otherwise healthy individuals, to the extent that CA-MRSA has become epidemic in the US and is now a public health imperative.  The recognition that CA-MRSA strains can both spread rapidly and cause severe disease mandates a need for urgent investigation to understand the molecular microbial pathogenicity and underlying host immune responses.  Our multidisciplinary team is composed of microbiologists, infectious disease experts, and immunologists to explore simultaneously several areas likely to yield important insights into the biology of the CA-MRSA epidemic, with a focus on the role of host immune responses in CA-MRSA infection.  Our studies have the potential to provide substantial insight into the contributions of host innate and adaptive mechanisms to infection susceptibility.  It is hoped that new information will guide novel therapeutic and preventive strategies to combat CA-MRSA infection.