Multipotent Adult Progenitor Cells Suppress T Cell Activation in In Vivo Models of Homeostatic Proliferation in a Prostaglandin E2-Dependent Manner

Abstract Multipotent adult progenitor cells (MAPCs) are nonhematopoietic stem cells capable of giving rise to a broad range of tissue cells. As such, MAPCs hold promise for tissue injury repair after transplant. In vitro, MAPCs potently suppressed allogeneic T-cell activation and proliferation in a dose-dependent, cell contact–independent, and T-regulatory cell–independent manner. Suppression occurred primarily through prostaglandin E2 synthesis in MAPCs, which resulted in decreased proinflammatory cytokine production. When given systemically, MAPCs did not home to sites of allopriming and did not suppress graft-versus-host disease (GVHD). To ensure that MAPCs would colocalize with donor T cells, MAPCs were injected directly into the spleen at bone marrow transplantation. MAPCs limited donor T-cell proliferation and GVHD-induced injury via prostaglandin E2 synthesis in vivo. Moreover, MAPCs altered the balance away from positive and toward inhibitory costimulatory pathway expression in splenic T cells and antigen-presenting cells. These findings are the first to describe the immunosuppressive capacity and mechanism of MAPC-induced suppression of T-cell alloresponses and illustrate the requirement for MAPC colocalization to sites of initial donor T-cell activation for GVHD inhibition. Such data have implications for the use of allogeneic MAPCs and possibly other immunomodulatory nonhematopoietic stem cells for preventing GVHD in the clinic.

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Tofacitinib Ameliorates Lupus Through Suppression of T Cell Activation Mediated by TGF-Beta Type I Receptor

Frontiers in Immunology ◽

10.3389/fimmu.2021.675542 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qing Yan ◽

Weiwei Chen ◽

Hua Song ◽

Xianming Long ◽

Zhuoya Zhang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Lupus Erythematosus ◽

Cell Activation ◽

Type I ◽

Dependent Manner ◽

Dsdna Antibody

Autoreactive T cells play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). TGF-β type I receptor (TGFβRI) is pivotal in determining T cell activation. Here, we showed that TGFβRI expression in naïve CD4+ T cells was decreased in SLE patients, especially in those with high disease activity. Moreover, IL-6 was found to downregulate TGFβRI expression through JAK/STAT3 pathway in SLE patients. In vitro, the JAK inhibitor tofacitinib inhibited SLE T cell activating by upregulating TGFβRI expression in a dose-dependent manner. In MRL/lpr mice, tofacitinib treatment ameliorated the clinical indicators and lupus nephritis, as evidenced by reduced plasma anti-dsDNA antibody levels, decreased proteinuria, and lower renal histopathological score. Consistently, tofacitinib enhanced TGFβRI expression and inhibited T cell activation in vivo. TGFβRI inhibitor SB431542 reversed the effects of tofacitinib on T cell activation. Thus, our results have indicated that tofacitinib can suppress T cell activation by upregulating TGFβRI expression, which provides a possible molecular mechanism underlying clinical efficacy of tofacitinib in treating SLE patients.

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CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1414576112 ◽

2014 ◽

Vol 112 (2) ◽

pp. 524-529 ◽

Cited By ~ 102

Author(s):

Chun Jing Wang ◽

Frank Heuts ◽

Vitalijs Ovcinnikovs ◽

Lukasz Wardzinski ◽

Chantelle Bowers ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

T Cell Responses ◽

Dependent Manner ◽

Cell Responses ◽

Follicular Helper ◽

Follicular Helper T Cell

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, and its absence precipitates lethal T-cell hyperactivity. However, whether CTLA-4 acts simply to veto the activation of certain clones or plays a more nuanced role in shaping the quality of T-cell responses is not clear. Here we report that T cells in CTLA-4–deficient mice show spontaneous T-follicular helper (TFH) differentiation in vivo, and this is accompanied by the appearance of large germinal centers (GCs). Remarkably, short-term blockade with anti–CTLA-4 antibody in wild-type mice is sufficient to elicit TFH generation and GC development. The latter occurs in a CD28-dependent manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway. CTLA-4 can act by down-regulating CD80 and CD86 on antigen presenting cells (APCs), thereby altering the level of CD28 engagement. To mimic reduced CD28 ligation, we used mice heterozygous for CD28, revealing that the magnitude of CD28 engagement is tightly linked to the propensity for TFH differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered TFH generation as a result of graded reduction in CD28 was associated with decreased numbers of GC B cells and a reduction in overall GC size. These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell priming and encompasses the regulation of TFH differentiation by graded control of CD28 engagement.

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Spinophilin participates in information transfer at immunological synapses

The Journal of Cell Biology ◽

10.1083/jcb.200711149 ◽

2008 ◽

Vol 181 (2) ◽

pp. 203-211 ◽

Cited By ~ 22

Author(s):

Ona Bloom ◽

Julia J. Unternaehrer ◽

Aimin Jiang ◽

Jeong-Sook Shin ◽

Lélia Delamarre ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Information Transfer ◽

Cell Activation ◽

Immunological Synapse ◽

Scaffolding Protein ◽

Dependent Manner ◽

Immunological Synapses

The adaptive immune response is initiated by the presentation of peptides bound to major histocompatibility complex molecules on dendritic cells (DCs) to antigen-specific T lymphocytes at a junction termed the immunological synapse. Although much attention has been paid to cytoplasmic events on the T cell side of the synapse, little is known concerning events on the DC side. We have sought signal transduction components of the neuronal synapse that were also expressed by DCs. One such protein is spinophilin, a scaffolding protein of neuronal dendritic spines that regulates synaptic transmission. In inactive, immature DCs, spinophilin is located throughout the cytoplasm but redistributes to the plasma membrane upon stimulus-induced maturation. In DCs interacting with T cells, spinophilin is polarized dynamically to contact sites in an antigen-dependent manner. It is also required for optimal T cell activation because DCs derived from mice lacking spinophilin exhibit defects in antigen presentation both in vitro and in vivo. Thus, spinophilin may play analogous roles in information transfer at both neuronal and immunological synapses.

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Sex Matters: Physiological Abundance of Immuno-Regulatory CD71+ Erythroid Cells Impair Immunity in Females

Frontiers in Immunology ◽

10.3389/fimmu.2021.705197 ◽

2021 ◽

Vol 12 ◽

Author(s):

Siavash Mashhouri ◽

Petya Koleva ◽

Mai Huynh ◽

Isobel Okoye ◽

Shima Shahbaz ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

The Body ◽

Dependent Manner ◽

Erythroid Cells ◽

Female Mice ◽

Wide Range ◽

Arginase Ii

Mature erythrocytes are the major metabolic regulators by transporting oxygen throughout the body. However, their precursors and progenitors defined as CD71+ Erythroid Cells (CECs) exhibit a wide range of immunomodulatory properties. Here, we uncover pronounced sexual dimorphism in CECs. We found female but not male mice, both BALB/c and C57BL/6, and human females were enriched with CECs. CECs, mainly their progenitors defined as CD45+CECs expressed higher levels of reactive oxygen species (ROS), PDL-1, VISTA, Arginase II and Arginase I compared to their CD45− counterparts. Consequently, CECs by the depletion of L-arginine suppress T cell activation and proliferation. Expansion of CECs in anemic mice and also post-menstrual cycle in women can result in L-arginine depletion in different microenvironments in vivo (e.g. spleen) resulting in T cell suppression. As proof of concept, we found that anemic female mice and mice adoptively transferred with CECs from anemic mice became more susceptible to Bordetella pertussis infection. These observations highlight the role of sex and anemia-mediated immune suppression in females. Notably, enriched CD45+CECs may explain their higher immunosuppressive properties in female BALB/c mice. Finally, we observed significantly more splenic central macrophages in female mice, which can explain greater extramedullary erythropoiesis and subsequently abundance of CECs in the periphery. Thus, sex-specific differences frequency in the frequency of CECs might be imprinted by differential erythropoiesis niches and hormone-dependent manner.

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Human Endothelial Cells Enhance Human Immunodeficiency Virus Type 1 Replication in CD4+ T Cells in a Nef-Dependent Manner In Vitro and In Vivo

Journal of Virology ◽

10.1128/jvi.79.1.264-276.2005 ◽

2005 ◽

Vol 79 (1) ◽

pp. 264-276 ◽

Cited By ~ 20

Author(s):

Jaehyuk Choi ◽

Jason Walker ◽

Sergei Boichuk ◽

Nancy Kirkiles-Smith ◽

Nicholas Torpey ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Dependent Manner ◽

Wild Type ◽

Mhc Ii ◽

Hiv 1

ABSTRACT Infected CD4+ T cells are the primary sites of human immunodeficiency virus type 1 (HIV-1) replication in vivo. However, signals from professional antigen-presenting cells (APCs), such as dendritic cells and macrophages, greatly enhance HIV-1 replication in T cells. Here, we report that in cocultures, vascular endothelial cells (ECs), which in humans can also serve as APCs, can enhance HIV-1 production of both CCR5- and CXCR4-utilizing strains approximately 50,000-fold. The observed HIV-1 replication enhancement conferred by ECs occurred only in memory CD4+ T cells, required expression of major histocompatibility complex class II (MHC-II) molecules by the ECs, and could not be conferred by fixed ECs, all of which are consistent with a requirement for EC-mediated T-cell activation via T-cell receptor (TCR) signaling. Deletion of nef (Nef−) decreased HIV-1 production by approximately 100-fold in T cells cocultured with ECs but had no effect on virus production in T cells cocultured with professional APCs or fibroblasts induced to express MHC-II. Human ECs do not express B7 costimulators, but Nef− replication in CD4+-T-cell and EC cocultures could not be rescued by anti-CD28 antibody. ECs act in trans to enhance wild-type but not Nef− replication and facilitate enhanced wild-type replication in naïve T cells when added to T-cell or B-lymphoblastoid cell cocultures, suggesting that ECs also provide a TCR-independent signal to infected T cells. Consistent with these in vitro observations, wild-type HIV-1 replicated 30- to 50-fold more than Nef− in human T cells infiltrating allogeneic human skin grafts on human huPBL-SCID/bg mice, an in vivo model of T-cell activation by ECs. Our studies suggest that ECs, which line the entire cardiovascular system and are, per force, in frequent contact with memory CD4+ T cells, provide signals to HIV-1-infected CD4+ T cells to greatly enhance HIV-1 production in a Nef-dependent manner, a mechanism that could contribute to the development of AIDS.

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Combinatorial Control of Signal-Induced Exon Repression by hnRNP L and PSF

Molecular and Cellular Biology ◽

10.1128/mcb.00419-07 ◽

2007 ◽

Vol 27 (19) ◽

pp. 6972-6984 ◽

Cited By ~ 49

Author(s):

Alexis A. Melton ◽

Jason Jackson ◽

Jiarong Wang ◽

Kristen W. Lynch

Keyword(s):

T Cells ◽

Alternative Splicing ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Exon Skipping ◽

Dependent Manner

ABSTRACT Cells can regulate their protein repertoire in response to extracellular stimuli via alternative splicing; however, the mechanisms controlling this process are poorly understood. The CD45 gene undergoes alternative splicing in response to T-cell activation to regulate T-cell function. The ESS1 splicing silencer in CD45 exon 4 confers basal exon skipping in resting T cells through the activity of hnRNP L and confers activation-induced exon skipping in T cells via previously unknown mechanisms. Here we have developed an in vitro splicing assay that recapitulates the signal-induced alternative splicing of CD45 and demonstrate that cellular stimulation leads to two changes to the ESS1-bound splicing regulatory complex. Activation-induced posttranslational modification of hnRNP L correlates with a modest increase in the protein's repressive activity. More importantly, the splicing factor PSF is recruited to the ESS1 complex in an activation-dependent manner and accounts for the majority of the signal-regulated ESS1 activity. The associations of hnRNP L and PSF with the ESS1 complex are largely independent of each other, but together these proteins account for the total signal-regulated change in CD45 splicing observed in vitro and in vivo. Such a combinatorial effect on splicing allows for precise regulation of signal-induced alternative splicing.

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Efficient infection, activation, and impairment of pDCs in the BM and peripheral lymphoid organs during early HIV-1 infection in humanized rag2−/−γ C−/− mice in vivo

Blood ◽

10.1182/blood-2011-01-331173 ◽

2011 ◽

Vol 117 (23) ◽

pp. 6184-6192 ◽

Cited By ~ 31

Author(s):

Liguo Zhang ◽

Qi Jiang ◽

Guangming Li ◽

Jerry Jeffrey ◽

Grigoriy I. Kovalev ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Lymphoid Organs ◽

Cd4 T Cell ◽

Human Immune System ◽

Double Knockout ◽

In Vivo Models ◽

Hiv 1

AbstractAlthough plasmacytoid dendritic cells (pDCs) are involved in HIV-1 pathogenesis, the precise mechanism of interaction between pDCs and HIV-1 in vivo is not clear. The conflicting reports in HIV-1–infected patients highlight the importance of studying the interaction between HIV-1 and pDCs in relevant in vivo models. The rag2/γC double knockout (DKO) mouse supports reconstitution of a functional human immune system in central and peripheral lymphoid organs. We report here that functional pDCs were developed in the BM and peripheral lymphoid organs in humanized DKO (DKO-hu) mice. We show that pDCs from both BM and spleen were activated and productively infected during early HIV infection. The activation level of pDCs correlated with that of CD4+ T-cell activation and apoptosis. Although CD4+ T cells were preferentially depleted, pDCs were maintained but functionally impaired in the BM and spleen of HIV-infected DKO-hu mice. We conclude that HIV-1 can efficiently infect, activate, and impair pDCs in the BM and spleen, in correlation with CD4+ T-cell depletion. The humanized mouse will serve as a relevant model to investigate the development and function of pDCs and their role during HIV-1 pathogenesis in vivo.

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