Programming of Lymphocyte Responses to Activation: Extrinsic Factors, Provided Microenvironmentally, Confer Flexibility and Compartmentalization to T-Cell Function1

2015 ◽  
pp. 1-20
Author(s):  
Raymond A. Daynes ◽  
Barbara A. Araneo
Keyword(s):  
T Cell ◽  
Extrinsic Factors ◽  
Lymphocyte Responses

scholarly journals TNF-α in T lymphocytes attenuates renal injury and fibrosis during nephrotoxic nephritis

2020 ◽  
Vol 318 (1) ◽  
pp. F107-F116 ◽  
Author(s):  
Yi Wen ◽  
Nathan P. Rudemiller ◽  
Jiandong Zhang ◽  
Taylor Robinette ◽  
Xiaohan Lu ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Renal Injury ◽  
Kidney Injury ◽  
Mrna Levels ◽  
T Helper ◽  
T Helper 17 ◽  
Immune Mediated ◽  
Tnf Α ◽  
Lymphocyte Responses

Nephrotoxic serum nephritis (NTN) models immune-mediated human glomerulonephritis and culminates in kidney inflammation and fibrosis, a process regulated by T lymphocytes. TNF-α is a key proinflammatory cytokine that contributes to diverse forms of renal injury. Therefore, we posited that TNF-α from T lymphocytes may contribute to NTN pathogenesis. Here, mice with T cell-specific deletion of TNF-α (TNF TKO) and wild-type (WT) control mice were subjected to the NTN model. At 14 days after NTN, kidney injury and fibrosis were increased in kidneys from TNF TKO mice compared with WT mice. PD1+CD4+ T cell numbers and mRNA levels of IL-17A were elevated in NTN kidneys of TNF TKO mice, suggesting that augmented local T helper 17 lymphocyte responses in the TNF TKO kidney may exaggerate renal injury and fibrosis. In turn, we found increased accumulation of neutrophils in TNF TKO kidneys during NTN. We conclude that TNF-α production in T lymphocytes mitigates NTN-induced kidney injury and fibrosis by inhibiting renal T helper 17 lymphocyte responses and infiltration of neutrophils.

scholarly journals Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

2020 ◽  
Author(s):  
Amania A. Sheikh ◽  
Joanna R. Groom
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Inflammatory Responses ◽  
Immune Memory ◽  
Transcriptional Networks ◽  
T Helper ◽  
T Helper 1 ◽  
Extrinsic Factors ◽  
Tfh Cells ◽  
Follicular Helper

Abstract During viral infection, immune cells coordinate the induction of inflammatory responses that clear infection and humoral responses that promote protection. CD4+ T-cell differentiation sits at the center of this axis. Differentiation toward T-helper 1 (Th1) cells mediates inflammation and pathogen clearance, while T follicular helper (Tfh) cells facilitate germinal center (GC) reactions for the generation of high-affinity antibodies and immune memory. While Th1 and Tfh differentiation occurs in parallel, these CD4+ T-cell identities are mutually exclusive, and progression toward these ends is determined via the upregulation of T-bet and Bcl6, respectively. These lineage-defining transcription factors act in concert with multiple networks of transcriptional regulators that tip the T-bet and Bcl6 axis in CD4+ T-cell progenitors to either a Th1 or Tfh fate. It is now clear that these transcriptional networks are guided by cytokine cues that are not only varied between distinct viral infections but also dynamically altered throughout the duration of infection. Thus, multiple intrinsic and extrinsic factors combine to specify the fate, plasticity, and function of Th1 and Tfh cells during infection. Here, we review the current information on the mode of action of the lineage-defining transcription factors Bcl6 and T-bet and how they act individually and in complex to govern CD4+ T-cell ontogeny. Furthermore, we outline the multifaceted transcriptional regulatory networks that act upstream and downstream of Bcl6 and T-bet to tip the differentiation equilibrium toward either a Tfh or Th1 fate and how these are impacted by dynamic inflammatory cues.

scholarly journals Cutaneous Lymphomas in European Pet Rabbits (Oryctolagus cuniculus)

2012 ◽  
Vol 49 (5) ◽  
pp. 846-851 ◽  
Author(s):  
J. M. Ritter ◽  
W. von Bomhard ◽  
A. G. Wise ◽  
R. K. Maes ◽  
M. Kiupel
Keyword(s):  
T Cell ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Cutaneous Lymphoma ◽  
World Health ◽  
B Cell Lymphomas ◽  
Viral Etiology ◽  
Extrinsic Factors ◽  
Cutaneous Lymphomas ◽  
Large B Cell

Cutaneous lymphoma is a common skin neoplasm of pet rabbits in Europe but is rarely reported in pet rabbits in North America. These neoplasms have not been previously characterized, nor has the cause for the apparent predilection for cutaneous lymphoma in European pet rabbits compared with North American pet rabbits been investigated. In this retrospective study, the authors morphologically and immunohistochemically characterized 25 cutaneous lymphomas in European pet rabbits according to the World Health Organization classification. Tumors were classified as diffuse large B cell lymphomas, with 14 lymphomas exhibiting a centroblastic/centrocytic subtype and 11 tumors exhibiting a T cell–rich B cell subtype. To investigate a potential viral etiology of these lymphomas, 3 diffuse large B cell and 3 T cell–rich B cell lymphomas were evaluated by polymerase chain reaction for retroviral and herpesviral genes. Neither virus was detected. In contrast to other domestic animals, cutaneous lymphomas in European pet rabbits were highly pleomorphic and frequently contained multinucleated giant cells. Unexpectedly, the second most common subtype was T cell–rich B cell lymphoma, a subtype that is rare in species other than horses. Based on a limited number of samples, there was no support for a viral etiology that would explain the higher incidence of lymphoma in European pet rabbits compared with American pet rabbits. Further investigation into genetic and extrinsic factors associated with the development of these tumors is warranted.

scholarly journals CD4+ T cell-released exosomes inhibit CD8+ cytotoxic T-lymphocyte responses and antitumor immunity

2010 ◽  
Vol 8 (1) ◽  
pp. 23-30 ◽  
Author(s):  
Haifeng Zhang ◽  
Yufeng Xie ◽  
Wei Li ◽  
Rajni Chibbar ◽  
Sidong Xiong ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Antitumor Immunity ◽  
Cytotoxic T Lymphocyte ◽  
Cd4 T Cell ◽  
Lymphocyte Responses

scholarly journals The lung vascular filter as a site of immune induction for T cell responses to large embolic antigen

2009 ◽  
Vol 206 (12) ◽  
pp. 2823-2835 ◽  
Author(s):  
Monique A.M. Willart ◽  
Hendrik Jan de Heer ◽  
Hamida Hammad ◽  
Thomas Soullié ◽  
Kim Deswarte ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Response ◽  
Bloodborne Pathogens ◽  
Cell Responses ◽  
Liver Sinusoids ◽  
A Site ◽  
Lymphocyte Responses

The bloodstream is an important route of dissemination of invading pathogens. Most of the small bloodborne pathogens, like bacteria or viruses, are filtered by the spleen or liver sinusoids and presented to the immune system by dendritic cells (DCs) that probe these filters for the presence of foreign antigen (Ag). However, larger pathogens, like helminths or infectious emboli, that exceed 20 µm are mostly trapped in the vasculature of the lung. To determine if Ag trapped here can be presented to cells of the immune system, we used a model of venous embolism of large particulate Ag (in the form of ovalbumin [OVA]-coated Sepharose beads) in the lung vascular bed. We found that large Ags were presented and cross-presented to CD4 and CD8 T cells in the mediastinal lymph nodes (LNs) but not in the spleen or liver-draining LNs. Dividing T cells returned to the lungs, and a short-lived infiltrate consisting of T cells and DCs formed around trapped Ag. This infiltrate was increased when the Toll-like receptor 4 was stimulated and full DC maturation was induced by CD40 triggering. Under these conditions, OVA-specific cytotoxic T lymphocyte responses, as well as humoral immunity, were induced. The T cell response to embolic Ag was severely reduced in mice depleted of CD11chi cells or Ly6C/G+ cells but restored upon adoptive transfer of Ly6Chi monocytes. We conclude that the lung vascular filter represents a largely unexplored site of immune induction that traps large bloodborne Ags for presentation by monocyte-derived DCs.

scholarly journals Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL

2020 ◽  
Vol 4 (3) ◽  
pp. 560-572 ◽  
Author(s):  
Rakesh Awasthi ◽  
Lida Pacaud ◽  
Edward Waldron ◽  
Constantine S. Tam ◽  
Ulrich Jäger ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Statistical Significance ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Extrinsic Factors ◽  
Cellular Kinetics

Abstract The anti-CD19 chimeric antigen receptor (CAR)–T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

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