IL-7– and IL-15–Mediated TCR Sensitization Enables T Cell Responses to Self-Antigens

Deshpande, Pratima; Cavanagh, Mary; Saux, Sabine Le; Singh, Karnail; Weyand, Cornelia M.; Goronzy, Jörg J.

doi:10.4049/jimmunol.1201620

Cited by 74 publications

(91 citation statements)

References 64 publications

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“…T-lymphocytes are relevant for cytopenias and other autoimmune features of several disorders including RA, SLE and Felty’s syndrome 1, 53 . Underlying mechanisms contributing to selective accumulation of leukemic LGL cells in the BM is unknown.…”

Section: Discussionmentioning

confidence: 99%

Fibrosis and Subsequent Cytopenias Are Associated with Basic Fibroblast Growth Factor–Deficient Pluripotent Mesenchymal Stromal Cells in Large Granular Lymphocyte Leukemia

Mailloux

Zhang

Moscinski

et al. 2013

The Journal of Immunology

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Cytopenias occur frequently in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Felty’s Syndrome and Large Granular Lymphocyte (LGL) leukemia, but the bone marrow microenvironment has not been systematically studied. In LGL leukemia (n=24), retrospective analysis of bone marrow (BM) histopathology revealed severe fibrosis in 15 out of 24 patients (63%) in association with the presence of cytopenias, occurrence of autoimmune diseases, and splenomegaly, but was undetectable in control cases with B-cell malignancies (n=11). Fibrosis severity correlated with T-LGL cell numbers in the BM but not in the periphery, suggesting deregulation is limited to the BM microenvironment. To identify fibrosis initiating populations, primary mesenchymal stromal cultures (MSCs) from patients were characterized and found to display proliferation kinetics and overabundant collagen deposition, but displayed normal telomere lengths and osteoblastogenic, chondrogenic, and adipogenic differentiation potentials. To determine the effect of fibrosis on healthy hematopoietic cells (HPCs), bioartificial matrixes from rat-tail or purified human collagen were found to suppress HPC differentiation and proliferation. The ability of patient MSCs to support healthy HSC proliferation was significantly impaired, but could be rescued with collagenase pre-treatment. Clustering analysis confirmed the undifferentiated state of patient MSCs, and pathway analysis revealed an inverse relationship between cell division and pro-fibrotic ontologies associated with reduced basic fibroblast growth factor (FGFb) production, which was confirmed by ELISA. Reconstitution with exogenous FGFb normalized patient MSC proliferation, collagen deposition, and HPC supportive function suggesting LGL BM infiltration and secondary accumulation of MSC-derived collagen is responsible for hematopoietic failure in autoimmune-associated cytopenias in LGL leukemia.

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Section: Discussionmentioning

confidence: 99%

Fibrosis and Subsequent Cytopenias Are Associated with Basic Fibroblast Growth Factor–Deficient Pluripotent Mesenchymal Stromal Cells in Large Granular Lymphocyte Leukemia

Mailloux

Zhang

Moscinski

et al. 2013

The Journal of Immunology

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“…IL-7 signaling could augment the pool of antigen-specific T cells by promoting survival of naive CD4 ϩ T cells and CD8 ϩ T cells or by preventing apoptosis of activated T cells in the proliferative pool (31,32). IL-7 is also known to costimulate T cell receptor (TCR) signaling (15,33) and to sensitize TCR thresholds (34), which may facilitate the proliferation of CD4 ϩ T cells into Tfh cells. In our present study, expressing IL-7 significantly increased the populations of Tfh cells, which are specialized supporters of B cells and important for the formation of GCs.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Interleukin-7 Extends the Humoral Immune Response Induced by Rabies Vaccination

Zhou

Luo

et al. 2017

J Virol

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Rabies continues to present a public health threat in most countries of the world. The most efficient way to prevent and control rabies is to implement vaccination programs for domestic animals. However, traditional inactivated vaccines used in animals are costly and have relatively low efficiency, which impedes their extensive use in developing countries. There is, therefore, an urgent need to develop single-dose and long-lasting rabies vaccines. However, little information is available regarding the mechanisms underlying immunological memory, which can broaden humoral responses following rabies vaccination. In this study, a recombinant rabies virus (RABV) that expressed murine interleukin-7 (IL-7), referred to here as rLBNSE-IL-7, was constructed, and its effectiveness was evaluated in a mouse model. rLBNSE-IL-7 induced higher rates of T follicular helper (Tfh) cells and germinal center (GC) B cells from draining lymph nodes (LNs) than the parent virus rLBNSE. Interestingly, rLBNSE-IL-7 improved the percentages of long-lived memory B cells (Bmem) in the draining LNs and plasma cells (PCs) in the bone marrow (BM) for up to 360 days postimmunization (dpi). As a result of the presence of the long-lived PCs, it also generated prolonged virus-neutralizing antibodies (VNAs), resulting in better protection against a lethal challenge than that seen with rLBNSE. Moreover, consistent with the increased numbers of Bmem and PCs after a boost with rLBNSE, rLBNSE-IL-7-immunized mice promptly produced a more potent secondary anti-RABV neutralizing antibody response than rLBNSE-immunized mice. Overall, our data suggest that overexpressing IL-7 improved the induction of long-lasting primary and secondary antibody responses post-RABV immunization.IMPORTANCE Extending humoral immune responses using adjuvants is an important method to develop long-lasting and efficient vaccines against rabies. However, little information is currently available regarding prolonged immunological memory post-RABV vaccination. In this study, a novel rabies vaccine that expressed murine IL-7 was developed. This vaccine enhanced the numbers of Tfh cells and the GC responses, resulting in upregulated quantities of Bmem and PCs. Moreover, we found that the long-lived PCs that were elicited by the IL-7-expressing recombinant virus (rLBNSE-IL-7) were able to sustain VNA levels much longer than those elicited by the parent rLBNSE virus. Upon reexposure to the pathogen, the longevous Bmem, which maintained higher numbers for up to 360 dpi with rLBNSE-IL-7 compared to rLBNSE, could differentiate into antibody-secreting cells, resulting in rapid and potent secondary production of VNAs. These results suggest that the expression of IL-7 is beneficial for induction of potent and long-lasting humoral immune responses.KEYWORDS IL-7, humoral immunity, rabies virus

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“…Such a function for the CD8αα homodimer based on the observation of a TCRαβ + CD8α + /CD8β-dim population in human intestine 36 is possible but yet to be demonstrated. The ability to recognize self-antigens is further enhanced when IL-15, 81 a cytokine induced under conditions of stress, inflammation and infection, is upregulated 80 , 82 , 83 . Of note, IL-15 46 , 48 and NKG2D 46 signaling in TCRαβ + CD8αβ + IEL induces effector programs that are not observed in memory TCRαβ + CD8αβ + T cells.…”

Section: Tcrab+cd8aa+/tcrab+cd8ab+ Iel and Autoreactivitymentioning

confidence: 99%

Human intraepithelial lymphocytes

Mayassi

Jabrì

2018

Mucosal Immunology

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The location of intraepithelial lymphocytes (IEL) between epithelial cells, their effector memory, cytolytic and inflammatory phenotype positions them to kill infected epithelial cells and protect the intestine against pathogens. Human TCRαβ+CD8αβ+ IEL have the dual capacity to recognize modified self via natural killer (NK) receptors (autoreactivity) as well as foreign antigen via the T cell receptor (TCR), which is accomplished in mouse by two cell subsets, the naturally occurring TCRαβ+CD8αα+ and adaptively induced TCRαβ+CD8αβ+ IEL subsets, respectively. The private/oligoclonal nature of the TCR repertoire of both human and mouse IEL suggests local environmental factors dictate the specificity of IEL responses. The line between sensing of foreign antigens and autoreactivity is blurred for IEL in celiac disease, where recognition of stress ligands by induced activating NK receptors in conjunction with inflammatory signals such as IL-15 can result in low-affinity TCR/non-cognate antigen and NK receptor/stress ligand interactions triggering destruction of intestinal epithelial cells.

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IL-7– and IL-15–Mediated TCR Sensitization Enables T Cell Responses to Self-Antigens

Cited by 74 publications

References 64 publications

Fibrosis and Subsequent Cytopenias Are Associated with Basic Fibroblast Growth Factor–Deficient Pluripotent Mesenchymal Stromal Cells in Large Granular Lymphocyte Leukemia

Fibrosis and Subsequent Cytopenias Are Associated with Basic Fibroblast Growth Factor–Deficient Pluripotent Mesenchymal Stromal Cells in Large Granular Lymphocyte Leukemia

Overexpression of Interleukin-7 Extends the Humoral Immune Response Induced by Rabies Vaccination

Human intraepithelial lymphocytes

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