Biomedical subjects

Tania S Gourley

Publications and source records attributed to Tania S Gourley.

7 recordsLinked to original sources

PubMed2006

Differentiation of memory B and T cells.

In the past few years progress has been made in understanding the molecular mechanisms that underlie the initial generation, and the ensuing differentiation and maintenance, of humoral and cellular immunity. Although B and T cell immunological memory contribute to protective immunity through fundamentally distinct effector functions, interesting analogies are becoming apparent between the two memory compartments. These include heterogeneity in function, anatomical location and phenotype, which probably relate to differential environmental cues during the early priming events as well as the later differentiation phases. Detailed definition of the molecular and cellular signals involved in the development of immunological memory, and the relative contributions of different memory subsets to protective immunity, remains an important goal.

Animals↗

PubMed2005

Constitutive expression of CIITA directs CD4 T cells to produce Th2 cytokines in the thymus.

We generated mice expressing a human type III CIITA transgene (CIITA Tg) under control of the CD4 promoter to study the role of CIITA in CD4 T cell biology. The transgene is expressed in peripheral CD4 and CD8 T cells, as well as in thymocytes. When CD4 T cells were differentiated towards the Th2 lineage, both control and CIITA Tg Th2 cells expressed similar levels of Th2 cytokines. Th1 cells from control and CIITA Tg mice cells produced comparable levels of IFN-gamma. CIITA Tg Th1 cells also expressed IL-4, IL-5, and IL-13 in the absence of Stat6. There was an approximate 10-fold increase in the number of peripheral naïve CD4 T cells and NK1.1- thymocytes producing IL-4 from CIITA Tg mice compared to control mice. Finally, Th1 cells from irradiated control mice reconstituted with CIITA Tg bone marrow displayed the same cytokine production profiles as Th1 cells from CIITA Tg mice. Together, our data demonstrate that CIITA expression pre-disposes CD4 T cells to produce Th2 type cytokines. Moreover, phenotypic similarities between Th1 cells expressing the CIITA transgene and CIITA deficient Th1 cells suggest that the role of CIITA in cytokine regulation is complex and may reflect both direct and indirect mechanisms of T cell development and differentiation.

Adoptive Transfer↗

PubMed2005

An alternate pathway for CD4 T cell development: thymocyte-expressed MHC class II selects a distinct T cell population.

Conventional understanding of CD4 T cell development is that the MHC class II molecules on cortical thymic epithelial cell are necessary for positive selection, as demonstrated in mouse models. Clinical data, however, show that hematopoietic stem cells reconstitute CD4 T cells in patients devoid of MHC class II. Additionally, CD4 T cells generated from human stem cells in immunocompromised mice were restricted to human, but not mouse, MHC class II. These studies suggest an alternative pathway for CD4 T cell development that does not normally exist in mice. MHC class II is expressed on developing human thymocytes, indicating a possible role of MHC II on thymocytes for CD4 T cell generation. Therefore, we created mice in which MHC class II is expressed only on T lineage cells. Remarkably, the CD4 compartment in such mice is efficiently reconstituted with unique specificity, demonstrating a novel thymocyte-driven pathway of CD4 T cell selection.

Animals↗

PubMed2004

Generation and maintenance of immunological memory.

The key feature of the adaptive immune response is its specificity and the ability to generate and maintain memory. Preexisting antibodies in the circulation and at the mucosa provide the first line of defense against re-infection by extracellular as well as intracellular pathogens. Memory T cells are an important second line of defense against intracellular pathogens, and in particular against microbes that can cause chronic or latent infection. In this article we will review our current understanding of the generation and maintenance of B cell and T cell memory.

Animals↗

PubMed2004

Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus.

Cap'n'collar (CNC) family basic leucine zipper transcription factors play crucial roles in the regulation of mammalian gene expression and development. To determine the in vivo function of the CNC protein Nrf3 (NF-E2-related factor 3), we generated mice deficient in this transcription factor. We performed targeted disruption of two Nrf3 exons coding for CNC homology, basic DNA-binding, and leucine zipper dimerization domains. Nrf3 null mice developed normally and revealed no obvious phenotypic differences compared to wild-type animals. Nrf3(-/-) mice were fertile, and gross anatomy as well as behavior appeared normal. The mice showed normal age progression and did not show any apparent additional phenotype during their life span. We observed no differences in various blood parameters and chemistry values. We infected wild-type and Nrf3(-/-) mice with acute lymphocytic choriomeningitis virus and found no differences in these animals with respect to their number of virus-specific CD8 and CD4 T cells as well as their B-lymphocyte response. To determine whether the mild phenotype of Nrf3 null animals is due to functional redundancy, we generated mice deficient in multiple CNC factors. Contrary to our expectations, an absence of Nrf3 does not seem to cause additional lethality in compound Nrf3(-/-)/Nrf2(-/-) and Nrf3(-/-)/p45(-/-) mice. We hypothesize that the role of Nrf3 in vivo may become apparent only after appropriate challenge to the mice.

Animals↗

PubMed2002

Aberrant expression of Fas ligand in mice deficient for the MHC class II transactivator.

The MHC class II transactivator (CIITA) is a critical regulator of MHC class II genes and other genes involved in the Ag presentation pathway. CIITA-deficient mice lack MHC class II expression on almost all APCs. In this study, we show that these mice also have aberrant Fas ligand expression on both CD4 T cells and B cells. We found that Fas ligand expression was greatly increased on CIITA-deficient CD4 T cells during the Th1 differentiation process. However, both CIITA-deficient and control Th1 effector cells up-regulated Fas ligand to similar levels if cells were reactivated. The introduction of CIITA into primary CD4 T cells via retroviral infection resulted in a reduction in the level of Fas ligand and delay in apoptosis after activation. Interestingly, activated B cells from the CIITA-deficient mice also showed increased levels of Fas ligand that could be to some degree inhibited by the introduction of IL-4.

Animals↗

PubMed2002

Function and regulation of class II transactivator in the immune system.

The class II transactivator (CIITA) is a potent and critical transcriptional regulator. It activates genes necessary for antigen presentation function. It also regulates cytokine gene expression in CD4 T cells. We recently found that CIITA prevents cell death by inhibiting Fas ligand (FasL) gene expression. Thus, CIITA regulates multiple immune responses. The activation and the repression function of CIITA are mediated by its interaction with other transcription factors. To activate the target gene, CIITA interacts with DNA binding proteins and recruits the coactivator CBP/p300 to the promoter forming an enhanceosome necessary for transcription. In addition, CIITA interacts with self. Inter- and intramolecular interactions of CIITA are essential for transactivation function. Each domain of CIITA has a distinct role and all domains are required for CIITA activity. However, the regulatory mechanisms of CIITA interaction with self and other proteins are poorly understood and remain to be investigated.

Animals↗