Follicular helper T (TFH) cells are critical for development of germinal center (GC) B cells responses following immunization with TD antigens and in systemic autoimmune responses;however, the development and function of these cells have been less clearly defined in both normal individuals and in patients with systemic lupus erythematosus than other CD4 T cell effector subsets. These issues have been a focus of study for the past several years, with characterization of CD4 T-B helper cells in murine models of lupus and in conventional immune responses, with the idea that information gleaned from the latter studies could be applied to the understanding of autoimmunity. The proposed work builds on these observations, and the more recent finding that TFH cells require the expression of the transcriptional repressor Bcl6 (B-cell CLL/lymphoma 6) for their development and for their function in B cell maturation in GCs - when upregulated in CD4 T cells, Bcl6 initiates a program of gene expression that drives a TFH cell phenotype. Preliminary studies have demonstrated that Bcl6 is also required for downregulation of P-selectin glycoprotein ligand-1 (PSGL1), a surface protein on T cells that engages the chemokines CCL19 and CCL21 expressed in the T cell zone of secondary lymphoid organs. Indeed, TFH cells in normal and systemic autoimmune responses are uniformly PSGL1lo. These observations suggest that downregulation of PSGL1 would disengage binding to these chemokines, allowing T zone egress with migration towards the B cell follicle where TFH cells are functionally required. This would support a scenario in which Bcl6, in its role as an initiator the TFH cell developmental program, is required for both T zone egress and for development of functional TFH cells. During these studies on TFH cell development and function, the transcription factor, Ascl2, a conserved member of the Drosophila Achaete scute-like 2 complex, was also found to be selectively upregulated in this T cell subset compared to other CD4 T cell effector subsets and compared to B cells. Expression of Ascl2 also is sufficient for development of a TFH cell phenotype. Based upon these findings, two hypotheses will be addressed in this proposal. First, PSGL1 acts as a retention signal for T cells in the T zone, and that in addition to driving TFH cell development, Bcl6 expression initiates downregulation of PSGL1 as a critical first step in T cell migration to the B cell follicle and ultimately in TFH cell function. Second, the transcription factor Ascl2, like Bcl6, plays a necessary role for TFH cell development and/or function. These hypotheses will be explored in two specific aims: 1) determining the roles of Bcl6 and PSGL1 in the initial events that lead to TFH cell migration and development;2) asking if the transcription factor Ascl2 is required for TFH cell differentiation and function, and if so, a dissection of the mechanism of its T cell-specific effects in immune responses.

Public Health Relevance

T cells that help B cells produce antibodies in the spleen and other lymphoid organs are critical for normal and autoimmune responses. In comparison to other types of T cells, less is known about the biology of these cells, including the signals that are required for their development and function. The results of the proposed studies, that utilize a combination of cellular, genetic, and imaging approaches, should help address these issues, and advance knowledge of how normal and autoimmune responses develop in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR040072-25
Application #
8654248
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
1990-08-31
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
25
Fiscal Year
2014
Total Cost
$350,330
Indirect Cost
$138,650
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Laidlaw, Brian J; Craft, Joseph E; Kaech, Susan M (2016) The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol 16:102-11
Marshall, Heather D; Ray, John P; Laidlaw, Brian J et al. (2015) The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa. Elife 4:e04851
Ray, John P; Staron, Matthew M; Shyer, Justin A et al. (2015) The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells. Immunity 43:690-702
Laidlaw, Brian J; Cui, Weiguo; Amezquita, Robert A et al. (2015) Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat Immunol 16:871-9
Brodeur, Tia Y; Robidoux, Tara E; Weinstein, Jason S et al. (2015) IL-21 Promotes Pulmonary Fibrosis through the Induction of Profibrotic CD8+ T Cells. J Immunol 195:5251-60
Choi, Jin-Young; Ho, John Hsi-en; Pasoto, Sandra G et al. (2015) Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol 67:988-99
Teichmann, Lino L; Cullen, Jaime L; Kashgarian, Michael et al. (2015) Local triggering of the ICOS coreceptor by CD11c(+) myeloid cells drives organ inflammation in lupus. Immunity 42:552-65
Ray, John P; Craft, Joe (2015) PTENtiating autoimmunity through Treg cell deregulation. Nat Immunol 16:139-40
Laidlaw, Brian J; Zhang, Nianzhi; Marshall, Heather D et al. (2014) CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41:633-45
Look, Michael; Saltzman, W Mark; Craft, Joe et al. (2014) The nanomaterial-dependent modulation of dendritic cells and its potential influence on therapeutic immunosuppression in lupus. Biomaterials 35:1089-95

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