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Scholarly Works (6 results)

  • Thesis
  • Peer Reviewed
UC Riverside Electronic Theses and Dissertations (2017)

T cells form a fundamental component of the protective response to chronic Toxoplasma gondii infection. The dire consequences of a failed T cell response in the protective response to this parasite are particularly apparent in AIDS patients, yet there must be a highly coordinated balance to the T cell response in the CNS. First, there must be a balance between pro-inflammatory and anti-inflammatory responses. Next, in a context of persistent antigen there must be a balance between the function of memory and effector subsets that simultaneously occupy the same niche. Finally, the T cell response must adapt to local conditions within the tissue. This dissertation explores these phenomena in the following ways:

In Chapter 1, we discuss what is known about the T cell response to Toxoplasma gondii infection. We explore the signals that determine infiltration into the brain, behavior within the brain, and phenotypic diversity. In Chapter 2, we discuss the role of tissue resident memory T cells in the protective response to chronic Toxoplasma gondii infection. Here we use RNA-Seq to determine that the distinct transcriptional profile of brain infiltrating CD103+ CD8 T cells is consistent with tissue resident memory T cells, or TRM. We then use re-stimulation assays to establish that this population has a significantly increased capacity to produce pro-inflammatory cytokines as compared to other populations within the brain. This data supports the presence of a functional population of memory T cells in the response to chronic Toxoplasma gondii infection.

In Chapter 3, we examine the requirement of lymph node homing dendritic cells expressing CCR7 for maintenance of effector T cells within the brain. This supports the requirement for ongoing recruitment of brain-infiltrating effector T cells. In Chapter 4 we examine how glutamate dysregulation within the CNS during chronic T. gondii infection impacts cytokine production and proliferation in activated T cells. We conclude in Chapter 5 by examining the common themes that emerge from the three primary chapters of the dissertation.

    Cover page: Local and Peripheral Cues Driving Heterogeneous Populations of Brain-Infiltrating T Cells During Chronic Toxoplasma gondii Infection
    • Article
    • Peer Reviewed
    UC Riverside Previously Published Works (2015)
    The rise of the AIDS epidemic made the requirement for T cells in our continuous protection from pathogens critically apparent. The striking frequency with which AIDS patients exhibited profound neurological pathologies brought attention to many chronic infections that are latent within the immune-privileged CNS. One of the most common lethal opportunistic infections of these patients was with the protozoan parasite, Toxoplasma gondii. Reactivation of Toxoplasma cysts within the brain causes massive tissue destruction evidenced as multiple ring-enhancing lesions on MRI and is called toxoplasmic encephalitis (TE). TE is not limited to AIDS patients, but rather is a risk for all severely immunocompromised patients, including recipients of chemotherapy or transplant recipients. The lessons learned from these patient populations are supported by T cell depletion studies in mice. Such experiments have demonstrated that CD4+ and CD8+ T cells are required for protection against TE. Although it is clear that these T cell subsets work synergistically to fight infection, much evidence has been generated that suggests CD8+ T cells play a dominant role in protection during chronic toxoplasmosis. In other models of CNS inflammation, such as intracerebral infection with LCMV and experimental autoimmune encephalomyelitis (EAE), infiltration of T cells into the brain is harmful and even fatal. In the brain of the immunocompetent host, the well-regulated T cell response to T. gondii is therefore an ideal model to understand a controlled inflammatory response to CNS infection. This review will examine our current understanding of CD8+ T cells in the CNS during T. gondii infection in regards to the (1) mechanisms governing entry into the brain, (2) cues that dictate behavior within the brain, and (3) the functional and phenotypic properties exhibited by these cells.
      Cover page: Characteristics and critical function of CD8+ T cells in the Toxoplasma-infected brain
      • Article
      • Peer Reviewed
      UC Riverside Previously Published Works (2017)
      During chronic infection, memory T cells acquire a unique phenotype and become dependent on different survival signals than those needed for memory T cells generated during an acute infection. The distinction between the role of effector and memory T cells in an environment of persistent antigen remains unclear. Here, in the context of chronic Toxoplasma gondii infection, we demonstrate that a population of CD8 T cells exhibiting a tissue-resident memory (TRM) phenotype accumulates within the brain. We show that this population is distributed throughout the brain in both parenchymal and extraparenchymal spaces. Furthermore, this population is transcriptionally distinct and exhibits a transcriptional signature consistent with the TRM observed in acute viral infections. Finally, we establish that the CD103+ TRM population has an intrinsic capacity to produce both IFN-γ and TNF-α, cytokines critical for parasite control within the central nervous system (CNS). The contribution of this population to pro-inflammatory cytokine production suggests an important role for TRM in protective and ongoing immune responses in the infected CNS. Accession number: GSE95105.
        Cover page: CD103+ CD8 T Cells in the Toxoplasma-Infected Brain Exhibit a Tissue-Resident Memory Transcriptional Profile
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2021)
        Central nervous system (CNS) injury and infection can result in profound tissue remodeling in the brain, the mechanism and purpose of which is poorly understood. Infection with the protozoan parasite Toxoplasma gondii causes chronic infection and inflammation in the brain parenchyma. Control of parasite replication requires the continuous presence of IFNγ-producing T cells to keep T. gondii in its slowly replicating cyst form. During infection, a network of extracellular matrix fibers, revealed using multiphoton microscopy, forms in the brain. The origin and composition of these structures are unknown but the fibers have been observed to act as a substrate for migrating T cells. In this study, we show a critical regulator of extracellular matrix (ECM) remodeling, Secreted Protein, Acidic, Rich in Cysteine (SPARC), is upregulated in the brain during the early phases of infection in the frontal cortex. In the absence of SPARC, a reduced and disordered fibrous network, increased parasite burden, and reduced antigen-specific T cell entry into the brain points to a role for SPARC in T cell recruitment to and migration within the brain. We also report SPARC can directly bind to CCR7 ligands CCL19 and CCL21 but not CXCL10, and enhance migration toward a chemokine gradient. Measurement of T cell behavior points to tissue remodeling being important for access of immune cells to the brain and facilitating cellular locomotion. Together, these data identify SPARC as an important regulatory component of immune cell trafficking and access to the inflamed CNS.
          Cover page: SPARC coordinates extracellular matrix remodeling and efficient recruitment to and migration of antigen-specific T cells in the brain following infection.
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2019)
          Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2019)
            Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
              Cover page: Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer
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