Shomyseh Sanjabi, Ph.D.
Assistant Investigator
Gladstone Institute of Virology and Immunology
Assistant Professor of Microbiology and Immunology
University of California, San Francisco
Email: shomyseh.sanjabi@gladstone.ucsf.edu
Telephone: 415-734-4814
Fax: 415-355-0153

In our lab, we study how the combination of inflammatory and anti-inflammatory cytokines dictates the quantity and quality of effector T cells under steady-state and inflammatory conditions in vivo. In particular, we focus on understanding the immune modulatory activity of transforming growth factor beta (TGFβ). TGFβ is a pleiotropic cytokine with potent regulatory and anti-inflammatory activity. The multi-faceted effects of TGFβ on numerous immune functions are cellular and environmental-context dependent. TGFβ is best known for its role in inducing peripheral tolerance by inhibiting the proliferation and differentiation of self-reactive CD4⁺ and CD8⁺ T cells. One of the mechanisms by which TGFβ is able to promote peripheral tolerance is to maintain the survival of naturally occurring Treg (nTreg) cells and to promote the differentiation of induced Treg (iTreg) cells. However, upon more systematic characterization of mice with a targeted deletion of TGFβ receptor on T cells (floxed TGFβ receptor II animals crossed to CD4-Cre), my colleagues and I discovered that TGFβ also controls peripheral tolerance by Treg-independent mechanisms. For example, TGFβ controls the survival of Th1 effector CD4⁺ T cells through controlling their responsiveness to IL-15. This phenomenon contributes to the inflammatory and multi-organ autoimmunity that develops in mice that lack TGFβ signaling in their T cells.

Recently, we showed that TGFβ also controls the number of CD8⁺ short-lived effector cells (SLECs) that are generated in response to a pathogenic infection. Naïve CD8⁺ T cells undergo a massive proliferation once they come in contact with their cognate antigen. This clonal expansion is followed by a contraction period where the majority of effector T cells die through apoptosis except for a small subset that survives and forms the memory pool. The effector T cells that survive contraction and live to form the memory pool are referred to as memory precursor effector cells (MPECs). Using T cells obtained from animals with genetic inhibition of TGFβ signaling in T cells, we demonstrated that TGFβ specifically promotes the apoptosis of SLECs during both clonal expansion and contraction, while IL-15 promoted their survival during contraction.

CLICK TO ENLARGE		TGFβ promotes the survival of naive T cells, but promotes the apoptosis of effector T cells. The immune system is maintained quiescent under steady state conditions. Normally, interactions between cells with T-cell receptors (TCR) and the major histocompatibility complex (MHC) containing only self-antigens result in the production of TGFβ but not IL-2. TGFβ inhibits full T-cell activation, proliferation, and differentiation and allows the T cells to receive only appropriate survival signals. However, when an infection occurs the T cell contacts an activated antigen-presenting cell (APC) displaying a foreign antigen, large amounts of IL-2 are produced. IL-2 neutralizes the inhibitory effects of TGFβ. TGFβ also controls the survivability of CD4+ Th1 cells by inhibiting T-bet, their master transcriptional regulator, which is required for expressing CD122 (IL-2 and IL-15Rβ), thus limiting their ability to respond to survival signals provided by IL-15. Meanwhile, TGFβ also inhibits expression of Bcl-2 in CD8+ effector T cells. Since short-lived effector cells (SLEC) lack IL-7Rα expression, they can only respond to IL-15 and therefore have lower levels of Bcl-2 than memory precursor effector cells (MPEC), which respond to IL-7 and IL-15. Thus, the decrease in Bcl-2 amounts by TGFβ has an apoptotic effect on SLECs: it lowers the level of Bcl-2 below the survival threshold, but the MPECs have enough Bcl-2 to allow them to survive and differentiate into memory cells.

Significance

Currently there are no vaccines available for many chronic viral infections such as HIV and HCV. Our studies will help in understanding the negative and positive signals that regulate the immune system. This knowledge will allow us to design better therapeutic strategies, such as vaccines, for chronic viral infections with the goal of eradicating disease affiliated with these infections.

Approaches

We use mouse genetic models, to study the role of pro- and anti-inflammatory cytokines in vivo. For example, to block TGFβ signaling specifically in T cells, we use a transgenic mouse that expresses a dominant negative form of TGFβ RII under the control of CD4 promoter. To block TGFβ signaling in other tissues, we use a TGFβ receptor floxed animal crossed to different Cre lines. We also use a variety of cellular immunology (i.e. adoptive cell transfer, bone marrow chimera, flow cytometry) and molecular biology (i.e. Quantitative RT-PCR, Western blotting, ELISA) techniques to address mechanistic questions

Contributions

• Mechanism of specificity among the NF-κB family of transcription factors
• TGFβ controls peripheral tolerance through Treg-dependent and –independent mechanisms
• TGFβ promotes the apoptosis of CD8⁺ T cells under inflammatory conditions

1. What is the cellular source of TGFβ under steady state and inflammatory conditions?
2. What is the role of TGFβ signaling in memory T cell development and function?
3. What is the interplay between TGFβ and the common gamma chain cytokines?
4. Can blocking TGFβ signaling lead to better therapeutic vaccines against chronic infections?
5. Does TGFβ play an inhibitory role during an adaptive immune response against HIV infection?

1. Flavell RA, Sanjabi S, Wrzesinski S, and Licona-Limon P. Polarization of immune cells in the tumour environment by TGF-beta. Nature Reviews Immunology. 2010, (In Press).
2. Sanjabi S, and Flavell RA. Interaction between TGF-beta and the common gamma chain cytokines during an inflammatory immune response. Cell Cycle. 2010, 9(3): 428-30.
3. Sanjabi S, Mosaheb MM, and Flavell RA. Opposing effects of TGF-beta and IL-15 cytokines control the number of short-lived effector CD8⁺ T cells. Immunity. 2009, 31(1):131-44.
4. Sanjabi S, Zenewicz LA, Kamanaka M, and Flavell RA. Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Current Opinion in Pharmacology. 2009, 9(4):447-53.
5. Li MO, Sanjabi S, and Flavell RA. Transforming Growth Factor-beta Controls Development, Homeostasis, and Tolerance of T Cells by Regulatory T Cell–Dependent and –Independent Mechanisms. Immunity. 2006, 25(3):455-71.
6. Li MO, Wan YY, Sanjabi S, Robertson AK, and Flavell RA. Transforming growth factor-beta regulation of immune responses. Annual Reviews of Immunology. 2006, 24: 99-146.