Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell–dendritic cell interactions

Interactions between dendritic cells (DCs) and T cells control the decision between activation and tolerance induction. Thromboxane A2 (TXA2) and its receptor TP have been suggested to regulate adaptive immune responses through control of T cell–DC interactions. Here, we show that this control is achieved by selectively reducing expansion of low-avidity CD4+ T cells. During inflammation, weak tetramer-binding TP-deficient CD4+ T cells were preferentially expanded compared with TP-proficient CD4+ T cells. Using intravital imaging of cellular interactions in reactive peripheral lymph nodes (PLNs), we found that TXA2 led to disruption of low- but not high-avidity interactions between DCs and CD4+ T cells. Lack of TP correlated with higher expression of activation markers on stimulated CD4+ T cells and with augmented accumulation of follicular helper T cells (TFH), which correlated with increased low-avidity IgG responses. In sum, our data suggest that tonic suppression of weak CD4+ T cell–DC interactions by TXA2–TP signaling improves the overall quality of adaptive immune responses.

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Faculty Opinions recommendation of T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718549286.793500135 ◽

2014 ◽

Author(s):

Torben Lund

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Cd8 T Cells ◽

T Cell Memory ◽

Adaptive Immune Responses ◽

Cell Memory ◽

Memory Cd8 T Cells ◽

Adaptive Immune

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SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis

10.1101/2020.02.21.959353 ◽

2020 ◽

Cited By ~ 2

Author(s):

Collin R Diedrich ◽

Tara Rutledge ◽

Pauline Maiello ◽

Tonilynn M Baranowski ◽

Alexander G White ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Risk Factor ◽

T Cell ◽

Immune Responses ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Bacterial Burden ◽

Common Risk Factor ◽

Immunodeficiency Virus

AbstractHuman immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-α, IFN-γ, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to Mtb/αCD4 animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.Author SummaryMost humans are able to control infection with Mycobacterium tuberculosis (Mtb), the bacteria that causes tuberculosis (TB). Controlled, asymptomatic infection (latent infection) can develop into symptomatic, severe TB (reactivation TB) when the immune system is impaired, and HIV is the most common risk factor. Chronic HIV infection is associated with low CD4 T cells but there are likely other factors involved. Using macaques with latent Mtb infection, we could induce reactivation from either CD4 T cell depletion or SIV infection. We found that SIV induced reactivation was more dramatic with more bacterial dissemination and bacterial growth compared to those with CD4 depletion. While SIV-infected animals had more activated immune responses in the lung granulomas (a collection of immune cells that functions to combat Mtb), they could not prevent bacterial spread of Mtb resulting in more TB pathology, higher bacterial burden and disease throughout the body. These data suggest that the HIV-induced reactivation TB is not solely from the loss of CD4 T cells. Furthermore, our data suggest that SIV and Mtb have a synergistic relationship within granulomas that impairs the ability to kill Mtb and that this relationship exacerbates TB disease.

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Relation of CD4+CD25+ Regulatory T Cells to Immune Status in Patients with HIV Infection.

Blood ◽

10.1182/blood.v104.11.3106.3106 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3106-3106

Author(s):

Sachi Tsunemi ◽

Tsuyoshi Iwasaki ◽

Takehito Imado ◽

Satoshi Higasa ◽

Eizo Kakishita ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Hiv Infection ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Healthy Controls ◽

Cell Counts ◽

Hiv 1

Abstract Human immunodeficiency virus (HIV) infection is characterized by marked defects in CD4+ helper T cell (Th) functions that commonly progress to a substantial decline in peripheral CD4+ T cell counts. However, the mechanisms responsible for the loss of Th functions in HIV-infected patients independent of CD4+ T cell counts remains unclear. CD4+CD25+ regulatory T cells (T Reg) are essential for down-regulation of both autoreactive and alloreactive T cells. Therefore, we decided to investigate the role of T Reg in immune status of HIV-infected patients. We examined the expression of cell surface CD25, cytoplasmic IL-4 and cytoplasmic IFN-gamma in peripheral blood CD4+ T cells from both healthy controls (n=9) and HIV-infected patients (n=43). We also compared T Reg functions between the 2 groups. CD4+CD25+ T Reg isolated from both HIV-infected patients and healthy controls strongly expressed CD45RO, HLA-DR, and FoxP3, and suppressed the proliferation of CD4+CD25− T cells, suggesting that CD4+CD25+ T cells from both healthy controls and HIV-infected patients possess phenotypic and functional characteristics of Treg. CD4+CD25high T cells are a subset of circulating CD4+CD25+ T cells in normal humans and exhibit strong in vitro regulatory functions similar to those reported for murine CD4+CD25+ T Reg. We measured the frequency of CD4+CD25high T Reg by analysis of surface CD25 on CD4+ T cells in peripheral blood samples. We also examined Th1 and Th2 frequencies by analysis of cytoplasmic IFN-gamma and IL-4 levels in CD4+ T cells. T Reg from HIV-infected patients with detectable plasma HIV-1 RNA showed a statistically significant increase in CD4+CD25high cell frequency (p<0.05) compared to healthy controls, with T Reg frequencies inversely proportional to CD4+ T cell numbers (p<0.01). However, in HIV-infected patients with undetectable plasma HIV-RNA, frequencies of CD4+CD25high T Reg were not increased and not related to CD4+ T cell numbers. In both HIV-infected patient groups, T Reg frequency was inversely related to Th1 frequency (detectable: p<0.05, undetectable: p<0.001), but positively related to Th2 frequency (detectable: p<0.01, undetectable: p<0.001). Our results indicate that increased frequencies of peripheral blood T Reg were related to disease progression as measured by detectable plasma HIV-1 RNA, decreased peripheral blood CD4+ T cell counts, and polarization toward Th2 immune responses in HIV-infected patients. HIV infection may lead to induction of T reg that inhibit antiviral immune responses, resulting in the progression of the disease. Manipulation of T Reg could help restore antiviral immune responses in HIV infection, and prevent the progression of HIV infection.

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Intestinal CD4 Depletion in HIV / SIV Infection

Current Immunology Reviews ◽

10.2174/1573395514666180605083448 ◽

2019 ◽

Vol 15 (1) ◽

pp. 76-91

Author(s):

Ronald S. Veazey

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Hiv Infection ◽

Viral Replication ◽

Cd4 T Cells ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Target Cells ◽

Mucosal Integrity

Among the most significant findings in the pathogenesis of HIV infection was the discovery that almost total depletion of intestinal CD4+ T cells occurs rapidly after SIV or HIV infection, regardless of the route of exposure, and long before CD4+ T cell losses occur in blood or lymph nodes. Since these seminal discoveries, we have learned much about mucosal and systemic CD4+ T cells, and found several key differences between the circulating and intestinal CD4+ T cell subsets, both in phenotype, relative proportions, and functional capabilities. Further, specific subsets of CD4+ T cells are selectively targeted and eliminated first, especially cells critically important for initiating primary immune responses, and for maintenance of mucosal integrity (Th1, Th17, and Th22 cells). This simultaneously results in loss of innate immune responses, and loss of mucosal integrity, resulting in mucosal, and systemic immune activation that drives proliferation and activation of new target cells throughout the course of infection. The propensity for the SIV/HIV to infect and efficiently replicate in specific cells also permits viral persistence, as the mucosal and systemic activation that ensues continues to damage mucosal barriers, resulting in continued influx of target cells to maintain viral replication. Finally, infection and elimination of recently activated and proliferating CD4+ T cells, and infection and dysregulation of Tfh and other key CD4+ T cell results in hyperactive, yet non-protective immune responses that support active viral replication and evolution, and thus persistence in host tissue reservoirs, all of which continue to challenge our efforts to design effective vaccine or cure strategies.

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Faculty Opinions recommendation of T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718549286.793499717 ◽

2014 ◽

Author(s):

Adrian Erlebacher

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Cd8 T Cells ◽

T Cell Memory ◽

Adaptive Immune Responses ◽

Cell Memory ◽

Memory Cd8 T Cells ◽

Adaptive Immune

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CD1-restricted adaptive immune responses to Mycobacteria in human group 1 CD1 transgenic mice

Journal of Experimental Medicine ◽

10.1084/jem.20090898 ◽

2009 ◽

Vol 206 (11) ◽

pp. 2497-2509 ◽

Cited By ~ 73

Author(s):

Kyrie Felio ◽

Hanh Nguyen ◽

Christopher C. Dascher ◽

Hak-Jong Choi ◽

Sha Li ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Small Animal ◽

Mycobacterial Infection ◽

Cell Receptor ◽

Human Group ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Group 1

Group 1 CD1 (CD1a, CD1b, and CD1c)–restricted T cells recognize mycobacterial lipid antigens and are found at higher frequencies in Mycobacterium tuberculosis (Mtb)–infected individuals. However, their role and dynamics during infection remain unknown because of the lack of a suitable small animal model. We have generated human group 1 CD1 transgenic (hCD1Tg) mice that express all three human group 1 CD1 isoforms and support the development of group 1 CD1–restricted T cells with diverse T cell receptor usage. Both mycobacterial infection and immunization with Mtb lipids elicit group 1 CD1–restricted Mtb lipid–specific T cell responses in hCD1Tg mice. In contrast to CD1d-restricted NKT cells, which rapidly respond to initial stimulation but exhibit anergy upon reexposure, group 1 CD1–restricted T cells exhibit delayed primary responses and more rapid secondary responses, similar to conventional T cells. Collectively, our data demonstrate that group 1 CD1–restricted T cells participate in adaptive immune responses upon mycobacterial infection and could serve as targets for the development of novel Mtb vaccines.

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Failure of CD4 T Cell-Deficient Hosts To Control Chronic Nontyphoidal Salmonella Infection Leads to Exacerbated Inflammation, Chronic Anemia, and Altered Myelopoiesis

Infection and Immunity ◽

10.1128/iai.00417-20 ◽

2020 ◽

Vol 89 (1) ◽

pp. e00417-20

Author(s):

Wendy P. Loomis ◽

Martha A. Delaney ◽

Matthew L. Johnson ◽

Brad T. Cookson

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Immune Functions ◽

Salmonella Infection ◽

Chronic Anemia ◽

Splenic Sequestration ◽

Adaptive Immune

ABSTRACTImmunocompromised patients are more susceptible to recurrent nontyphoidal Salmonella (NTS) bacteremia. A key manifestation of HIV infection is the loss of CD4 T cells, which are crucial for immunity to Salmonella infection. We characterized the consequences of CD4 T cell depletion in mice where virulent Salmonella establish chronic infection, similar to chronic NTS disease in humans. Salmonella-infected, CD4-depleted 129X1/SvJ mice remained chronically colonized for at least 5 weeks, displaying increased splenomegaly and more severe splenitis than infected mice with CD4 T cells. Mature erythrocytes, immature erythroid cells, and phagocytes accounted for the largest increase in splenic cellularity. Anemia, which is associated with increased mortality in Salmonella-infected humans, was exacerbated by CD4 depletion in infected mice and was accompanied by increased splenic sequestration of erythrocytes and fewer erythropoietic elements in the bone marrow, despite significantly elevated levels of circulating erythropoietin. Splenic sequestration of red blood cells, the appearance of circulating poikilocytes, and elevated proinflammatory cytokines suggest inflammation-induced damage to erythrocytes contributes to anemia and splenic retention of damaged cells in infected animals. Depleting CD4 T cells led to increased myeloid cells in peripheral blood, spleen, and bone marrow, as well as expansion of CD8 T cells, which has been observed in CD4-depleted humans. This work describes a mouse model of Salmonella infection that recapitulates several aspects of human disease and will allow us to investigate the interplay of innate and adaptive immune functions with chronic inflammation, anemia, and susceptibility to Salmonella infection.

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Modulation of Vaccine-Induced CD4 T Cell Functional Profiles by Changes in Components of HIV Vaccine Regimens in Humans

Journal of Virology ◽

10.1128/jvi.01143-18 ◽

2018 ◽

Vol 92 (23) ◽

Cited By ~ 5

Author(s):

Franco Pissani ◽

Bianca Schulte ◽

Michael A. Eller ◽

Bruce T. Schultz ◽

Silvia Ratto-Kim ◽

...

Keyword(s):

Clinical Trials ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Hiv Infection ◽

Cd4 T Cells ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses ◽

Hiv 1

ABSTRACT To date, six vaccine strategies have been evaluated in clinical trials for their efficacy at inducing protective immune responses against HIV infection. However, only the ALVAC-HIV/AIDSVAX B/E vaccine (RV144 trial) has demonstrated protection, albeit modestly (31%; P = 0.03). One potential correlate of protection was a low-frequency HIV-specific CD4 T cell population with diverse functionality. Although CD4 T cells, particularly T follicular helper (Tfh) cells, are critical for effective antibody responses, most studies involving HIV vaccines have focused on humoral immunity or CD8 T cell effector responses, and little is known about the functionality and frequency of vaccine-induced CD4 T cells. We therefore assessed responses from several phase I/II clinical trials and compared them to responses to natural HIV-1 infection. We found that all vaccines induced a lower magnitude of HIV-specific CD4 T cell responses than that observed for chronic infection. Responses differed in functionality, with a CD40 ligand (CD40L)-dominated response and more Tfh cells after vaccination, whereas chronic HIV infection provoked tumor necrosis factor alpha (TNF-α)-dominated responses. The vaccine delivery route further impacted CD4 T cells, showing a stronger Th1 polarization after dendritic cell delivery than after intramuscular vaccination. In prime/boost regimens, the choice of prime and boost influenced the functional profile of CD4 T cells to induce more or less polyfunctionality. In summary, vaccine-induced CD4 T cell responses differ remarkably between vaccination strategies, modes of delivery, and boosts and do not resemble those induced by chronic HIV infection. Understanding the functional profiles of CD4 T cells that best facilitate protective antibody responses will be critical if CD4 T cell responses are to be considered a clinical trial go/no-go criterion. IMPORTANCE Only one HIV-1 candidate vaccine strategy has shown protection, albeit marginally (31%), against HIV-1 acquisition, and correlates of protection suggested that a multifunctional CD4 T cell immune response may be important for this protective effect. Therefore, the functional phenotypes of HIV-specific CD4 T cell responses induced by different phase I and phase II clinical trials were assessed to better show how different vaccine strategies influence the phenotype and function of HIV-specific CD4 T cell immune responses. The significance of this research lies in our comprehensive comparison of the compositions of the T cell immune responses to different HIV vaccine modalities. Specifically, our work allows for the evaluation of vaccination strategies in terms of their success at inducing Tfh cell populations.

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Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis

Blood ◽

10.1182/blood-2007-04-087171 ◽

2007 ◽

Vol 110 (10) ◽

pp. 3673-3681 ◽

Cited By ~ 51

Author(s):

Philip O. Scumpia ◽

Matthew J. Delano ◽

Kindra M. Kelly-Scumpia ◽

Jason S. Weinstein ◽

James L. Wynn ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Immune Dysfunction ◽

Effector Function ◽

Cd4 T Cell ◽

Agonistic Antibody ◽

Adaptive Immune ◽

Cell Effector Function ◽

Cell Effector

Abstract Apoptosis of CD4+ T cells and TH2 polarization are hallmarks of sepsis-induced immunoparalysis. In this study, we characterized sepsis-induced adaptive immune dysfunction and examined whether improving T-cell effector function can improve outcome to sepsis. We found that septic mice produced less antigen-specific T-cell–dependent IgM and IgG2a antibodies than sham-treated mice. As early as 24 hours after sepsis, CD4+ T cells proliferated poorly to T-cell receptor stimulation, despite normal responses to phorbol myristate acetate and ionomycin, and possessed decreased levels of CD3ζ. Five days following immunization, CD4+ T cells from septic mice displayed decreased antigen-specific proliferation and production of IL-2 and IFN-γ but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4+ T-cell proliferation, increased TH1 and TH2 cytokine production, partially prevented CD3ζ down-regulation, decreased bacteremia, and increased sepsis survival. Depletion of CD4+ T cells but not CD25+ regulatory T cells eliminated the survival benefit of anti-GITR treatment. These results indicate that CD4+ T-cell dysfunction is a key component of sepsis and that improving T-cell effector function may be protective against sepsis-associated immunoparalysis.

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