Effect of Inflammatory and Anti-inflammatory Cytokines on Effector T Cells Under Steady-state and Inflammatory Conditions in vivo

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Areas of Investigation
A healthy immune system maintains tolerance against autoreactive T cells under normal conditions, mounts an effective immune response against foreign antigens, and once the antigen has been cleared, it returns the immune cells back to their homeostatic state. Cytokines play a major role in maintaining lymphocyte homeostasis under both steady-state and inflammatory conditions. Unregulated autoreactive lymphocytes can cause autoimmunity, whereas unresponsive or exhausted lymphocytes can lead to uncontrolled infections or tumor development.

These areas of investigation address fundamentally important questions about lymphocyte development and function, but they also enhance our understanding of ways to develop better vaccines and strategies to improve immunomodulatory therapies for a fight against chronic pathogens/diseases, such as HIV/AIDS.

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.

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

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

 
Questions addressed in ongoing studies

  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?