Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production

In the present study, we have investigated the distribution of HIV-specific and HIV-infected CD4 T cells within different populations of memory CD4 T cells isolated from lymph nodes of viremic HIV-infected subjects. Four memory CD4 T cell populations were identified on the basis of the expression of CXCR5, PD-1, and Bcl-6: CXCR5−PD-1−Bcl-6−, CXCR5+PD-1−Bcl-6−, CXCR5−PD-1+Bcl-6−, and CXCR5+PD-1+Bcl-6+. On the basis of Bcl-6 expression and functional properties (IL-21 production and B cell help), the CXCR5+PD-1+Bcl-6+ cell population was considered to correspond to the T follicular helper (Tfh) cell population. We show that Tfh and CXCR5−PD-1+ cell populations are enriched in HIV-specific CD4 T cells, and these populations are significantly increased in viremic HIV-infected subjects as compared with healthy subjects. The Tfh cell population contained the highest percentage of CD4 T cells harboring HIV DNA and was the most efficient in supporting productive infection in vitro. Replication competent HIV was also readily isolated from Tfh cells in subjects with nonprogressive infection and low viremia (<1,000 HIV RNA copies). However, only the percentage of Tfh cells correlated with the levels of plasma viremia. These results demonstrate that Tfh cells serve as the major CD4 T cell compartment for HIV infection, replication, and production.

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CD32+and PD-1+Lymph Node CD4 T Cells Support Persistent HIV-1 Transcription in Treated Aviremic Individuals

Journal of Virology ◽

10.1128/jvi.00901-18 ◽

2018 ◽

Vol 92 (20) ◽

Cited By ~ 18

Author(s):

Alessandra Noto ◽

Francesco A. Procopio ◽

Riddhima Banga ◽

Madeleine Suffiotti ◽

Jean-Marc Corpataux ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hiv Infection ◽

Cell Population ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Cell Populations ◽

Latently Infected ◽

Infected Cells ◽

Hiv 1

ABSTRACTA recent study conducted in blood has proposed CD32 as the marker identifying the “elusive” HIV reservoir. We have investigated the distribution of CD32+CD4 T cells in blood and lymph nodes (LNs) of HIV-1-uninfected subjects and viremic untreated and long-term-treated HIV-1-infected individuals and their relationship with PD-1+CD4 T cells. The frequency of CD32+CD4 T cells was increased in viremic compared to treated individuals in LNs, and a large proportion (up to 50%) of CD32+cells coexpressed PD-1 and were enriched within T follicular helper (Tfh) cells. We next investigated the role of LN CD32+CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32+and PD-1+CD4 T cells compared to CD32−and PD-1−cells in both viremic and treated individuals, but there was no difference between CD32+and PD-1+cells. There was no enrichment of latently infected cells with inducible HIV-1 in CD32+versus PD-1+cells in antiretroviral therapy (ART)-treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32+PD-1+CD4 T cells were significantly enriched in cell-associated HIV RNA compared to CD32−PD-1−(averages of 5.2-fold in treated individuals and 86.6-fold in viremics), CD32+PD-1−(2.2-fold in treated individuals and 4.3-fold in viremics), and CD32−PD-1+(2.2-fold in ART-treated individuals and 4.6-fold in viremics) cell populations. Similar levels of HIV-1 transcription were found in CD32+PD-1−and CD32−PD-1+CD4 T cells. Interestingly, the proportion of CD32+and PD-1+CD4 T cells negatively correlated with CD4 T cell counts and length of therapy. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and coexpression of CD32 and PD-1, the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals.IMPORTANCEThe existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication-competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells coexpressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription.

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Expansion and tissue infiltration of an allospecific CD4+CD25+CD45RO+IL-7Rαhigh cell population in solid organ transplant recipients

Journal of Experimental Medicine ◽

10.1084/jem.20062120 ◽

2007 ◽

Vol 204 (7) ◽

pp. 1533-1541 ◽

Cited By ~ 40

Author(s):

Laura Codarri ◽

Laure Vallotton ◽

Donatella Ciuffreda ◽

Jean-Pierre Venetz ◽

Miguel Garcia ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Population ◽

Cd4 T Cells ◽

Chronic Rejection ◽

Healthy Subjects ◽

Cd4 T Cell ◽

Transplant Proc ◽

Cell Populations ◽

Transplant Recipients

It has been recently shown (Seddiki, N., B. Santner-Nanan, J. Martinson, J. Zaunders, S. Sasson, A. Landay, M. Solomon, W. Selby, S.I. Alexander, R. Nanan, et al. 2006. J. Exp. Med. 203:1693–1700.) that the expression of interleukin (IL) 7 receptor (R) α discriminates between two distinct CD4 T cell populations, both characterized by the expression of CD25, i.e. CD4 regulatory T (T reg) cells and activated CD4 T cells. T reg cells express low levels of IL-7Rα, whereas activated CD4 T cells are characterized by the expression of IL-7Rαhigh. We have investigated the distribution of these two CD4 T cell populations in 36 subjects after liver and kidney transplantation and in 45 healthy subjects. According to a previous study (Demirkiran, A., A. Kok, J. Kwekkeboom, H.J. Metselaar, H.W. Tilanus, and L.J. van der Laan. 2005. Transplant. Proc. 37:1194–1196.), we observed that the T reg CD25+CD45RO+IL-7Rαlow cell population was reduced in transplant recipients (P < 0.00001). Interestingly, the CD4+CD25+CD45RO+IL-7Rαhigh cell population was significantly increased in stable transplant recipients compared with healthy subjects (P < 0.00001), and the expansion of this cell population was even greater in patients with documented humoral chronic rejection compared with stable transplant recipients (P < 0.0001). The expanded CD4+CD25+CD45RO+IL-7Rαhigh cell population contained allospecific CD4 T cells and secreted effector cytokines such as tumor necrosis factor α and interferon γ, thus potentially contributing to the mechanisms of chronic rejection. More importantly, CD4+IL-7Rα+and CD25+IL-7Rα+ cells were part of the T cell population infiltrating the allograft of patients with a documented diagnosis of chronic humoral rejection. These results indicate that the CD4+CD25+IL-7Rα+ cell population may represent a valuable, sensitive, and specific marker to monitor allospecific CD4 T cell responses both in blood and in tissues after organ transplantation.

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CD32+and PD-1+Lymph Node CD4 T Cells Support Persistent HIV-1 Transcription in Treated Aviremic Individuals

10.1101/329938 ◽

2018 ◽

Cited By ~ 1

Author(s):

Alessandra Noto ◽

Francesco A. Procopio ◽

Riddhima Banga ◽

Madeleine Suffiotti ◽

Jean-Marc Corpataux ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hiv Infection ◽

Cell Population ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Cell Populations ◽

Latently Infected ◽

Infected Cells ◽

Hiv 1

ABSTRACTA recent study conducted in blood has proposed CD32 as the marker identifying the ‘elusive’ HIV reservoir. We have investigated the distribution of CD32+CD4 T cells in blood and lymph nodes(LNs) of healthy HIV-1 uninfected, viremic untreated and long-term treated HIV-1 infected individuals and their relationship with PD-1+CD4 T cells. The frequency of CD32+CD4 T cells was increased in viremic as compared to treated individuals in LNs and a large proportion(up to 50%) of CD32+cells co-expressed PD-1 and were enriched within T follicular helper cells(Tfh) cells. We next investigated the role of LN CD32+CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32+and PD-1+CD4 T cells as compared to CD32-and PD-1-cells in both viremic and treated individuals but there was no difference between CD32+and PD-1+cells. There was not enrichment of latently infected cells with inducible HIV-1 in CD32+versus PD-1+cells in ART treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32+PD-1+CD4 T cells were significantly enriched in cell associated HIV RNA as compared to CD32-PD-1-(average 5.2 fold in treated and 86.6 fold in viremics), to CD32+PD-1-(2.2 fold in treated and 4.3 fold in viremics) and to CD32-PD-1+cell populations(2.2 fold in ART treated and 4.6 fold in viremics). Similar levels of HIV-1 transcription were found in CD32+PD-1-and CD32-PD-1+CD4 T cells. Interestingly, the proportion of CD32+and PD-1+CD4 T cells negatively correlated with CD4 T cell counts and length of therapy while positively correlated with viremia. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and CD32 and PD-1 co-expression the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals.ImportanceThe existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells co-expressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription.

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A Variety of T-Cell Subsets Contribute to CD4+ T-Cell Infiltration in Diffuse Large B-Cell Lymphoma and Both Total CD4+ and CD4+FoxP3+ T-Cell Numbers Predict Clinical Outcome,

Blood ◽

10.1182/blood.v118.21.3684.3684 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3684-3684

Author(s):

Matthew J Ahearne ◽

Kaljit S Bhuller ◽

Roger Hew ◽

Giovanna Roncador ◽

Martin J.S. Dyer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Clinical Outcome ◽

Cd4 T Cells ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Cell Infiltration ◽

Good Clinical Outcome ◽

Logrank Test ◽

Tfh Cells

Abstract Abstract 3684 CD4+ T-cells can be distinguished into subsets on the basis of surface marker expression and growth factor production. Follicular helper T-cells (Tfh cells) are characterized by the co-expression of surface markers (CD4, ICOS, PD1 and CXCR5) and nuclear BCL6. Normal germinal centre formation requires Tfh cells but is repressed by another CD4+ T-cell subset, Tregs, (demonstrating CD4 and CD25 expression with nuclear FoxP3). The numbers and architecture of infiltrating T-cells predict clinical outcome in follicular lymphoma but although T-cells are a component of diffuse large B cell lymphoma (DLBCL), the relative numbers of CD4+ T-cells and their Tfh and Treg subsets or their association with clinical outcome is not known. We used immunohistochemistry to investigate infiltration by total CD4+, Treg and Tfh cells in cases (n=23) from one centre. The male:female was 1.3:1.0, the age range was 30 to 78 years (median 65 years) and the anticipated association between overall survival and LDH (logrank test, P=0.02) was observed. Patients were treated with R-CHOP with a 21-day cycle. Histological sections were stained with anti-CD4, anti-PD1 and anti-FoxP3 antibodies. For each antibody the area of staining was measured using ImageJ software from 10 high power fields from the same area of each histological section. Tfh cells were identified by strong surface expression of PD1 and Tregs by nuclear expression of FoxP3. CD4+ T-cell infiltration varied by ∼50-fold, and could be diffuse or focal. In 13 cases (57%) the majority of CD4+ T-cells were neither FoxP3+ nor PD1+. Total CD4+ T-cell numbers were positively correlated with FoxP3 (P=0.04) (Figure 1) and with PD1 (P=0.009) (Figure 2) expressing cells suggesting that these subsets were expanded as part of a reaction to the lymphoma capable of stimulating several CD4+ T-cell subsets. High CD4+ (Figure 3) and PD1+ staining predicted good clinical outcome (logrank test, P=0.08) with median survival not being reached at 5 years, but the amount of FoxP3+ staining appeared to be a superior prognostic marker (logrank test, P=0.0069) (Figure 4). There was no association between the cell of origin classification of DLBCL (GCB or ABC) as defined immunohistochemically, and CD4, FoxP3 or PD1 expression. In summary, we have shown that numbers of infiltrating CD4+ T-cells vary between cases of DLBCL and comprises several T-cell subsets including Treg and Tfh cells. No consensus has been reached on the clinical significance of FoxP3+ cell infiltration in DLBCL. Whilst some workers have shown FoxP3 to be associated with a good clinical outcome (Tzankov A., et al. 2008; Lee N., et al. 2008), others have not found a relationship to prognosis (Hasselblom S. et al., 2007). Our data shows that the FoxP3+ Treg cell subset is associated with good clinical outcome but surprisingly we found that both increased total CD4+ T-cells and PD1+ Tfh cells also carry a good prognosis. Disclosures: Wagner: Roche: Honoraria.

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Self-recognition drives the preferential accumulation of promiscuous CD4+ T-cells in aged mice

eLife ◽

10.7554/elife.05949 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 19

Author(s):

Neha R Deshpande ◽

Heather L Parrish ◽

Michael S Kuhns

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Biology ◽

Fold Increase ◽

Cell Receptor ◽

Cd4 T Cell ◽

Fundamental Aspect ◽

Cell Compartment ◽

Old Mice

T-cell recognition of self and foreign peptide antigens presented in major histocompatibility complex molecules (pMHC) is essential for life-long immunity. How the ability of the CD4+ T-cell compartment to bind self- and foreign-pMHC changes over the lifespan remains a fundamental aspect of T-cell biology that is largely unexplored. We report that, while old mice (18–22 months) contain fewer CD4+ T-cells compared with adults (8–12 weeks), those that remain have a higher intrinsic affinity for self-pMHC, as measured by CD5 expression. Old mice also have more cells that bind individual or multiple distinct foreign-pMHCs, and the fold increase in pMHC-binding populations is directly related to their CD5 levels. These data demonstrate that the CD4+ T-cell compartment preferentially accumulates promiscuous constituents with age as a consequence of higher affinity T-cell receptor interactions with self-pMHC.

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Age-Related Induction of CD4+ T-Cell Unresponsiveness Is Reversible and Dependant of the Host’s Environment.

Blood ◽

10.1182/blood.v106.11.3925.3925 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3925-3925

Author(s):

Pedro Horna ◽

Rahul Chavan ◽

Jason Brayer ◽

Ildefonso Suarez ◽

Eduardo M. Sotomayor

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Cell Compartment ◽

Memory Phenotype ◽

Age Related ◽

And Function

Abstract A large number of CD4+ T-cells from either aged mice or humans display surface markers associated with an activated/memory phenotype. In spite of these changes however, these T-cells have a markedly decreased ability to proliferate and produce IL-2 in response to antigen stimulation in vitro. The cellular and molecular mechanisms involved in this age-related unresponsiveness of the CD4+ T-cell compartment remain poorly understood. Utilizing a well-established experimental system in which transgenic CD4+ T cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA) are adoptively transferred into non-transgenic recipients, we have previously elucidated important mechanisms involved in the induction and maintenance of CD4+ T-cell tolerance. Our studies were however limited to the analysis of T-cell function in lymphoma bearing young mice (4 to 10 weeks old). Here, we assessed the influence of the aged microenvironment in determining the phenotype and function of antigen-specific T-cells. CD4+ T-cells from young TCR transgenic mice (2 months old) were adoptively transferred into either old (20–24 months) or young (2 months old) non-transgenic mice. Two weeks later, clonotypic and non-clonotypic CD4+ T-cells were isolated from the spleens of these animals and their phenotype and function were determined in vitro. Reminiscent of the age-related changes observed within the normal CD4+ T-cell repertoire, young transgenic T-cells transferred into aged hosts have acquired an activated/memory phenotype but displayed a significant impairment in antigen-specific proliferation and IL-2 production in response to cognate antigen in vitro. These changes were not due to homeostatic proliferation of the transferred T-cells into the relatively lymphopenic aged host. To determine whether the changes observed in “aged” T-cells were reversible or not, we adoptively transfer old T-cells back into young hosts or into control old mice. While old transgenic T-cells transferred into an old environment remained fully unresponsive, the adoptive transfer of the same old T-cells into a young host restored their ability to proliferate and produce IL-2. Surprisingly, these “old” T-cells were able to produce significantly higher levels of IFN-gamma indicative of their memory/effector phenotype. Furthermore, young animals adoptively transferred with “aged” antigen-specific T-cells were now capable of rejecting A20 B-cell lymphomas expressing HA as a model tumor antigen (A20HA). Taking together, factor(s) present in the aged microenvironment are responsible for limiting the effector function of CD4+ T-cells that seem otherwise well equipped to become fully activated if the proper environment is provided (young microenvironment). The potential role of soluble suppressive factors as well as regulatory T-cells (Tregs) in the unresponsiveness observed in the T-cell compartment of aged hosts will be discussed.

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Regulatory CD4 T Cells Control the Size of the Peripheral Activated/Memory CD4 T Cell Compartment

The Journal of Immunology ◽

10.4049/jimmunol.164.7.3573 ◽

2000 ◽

Vol 164 (7) ◽

pp. 3573-3580 ◽

Cited By ~ 110

Author(s):

Oliver Annacker ◽

Odile Burlen-Defranoux ◽

Ricardo Pimenta-Araujo ◽

Ana Cumano ◽

Antonio Bandeira

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Cell Compartment

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Self major histocompatibility complex class I antigens expressed solely in lymphoid cells do not induce tolerance in the CD4+ T cell compartment.

Journal of Experimental Medicine ◽

10.1084/jem.184.4.1573 ◽

1996 ◽

Vol 184 (4) ◽

pp. 1573-1578 ◽

Cited By ~ 11

Author(s):

R Schulz ◽

A L Mellor

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Lymphoid Cells ◽

Cd4 T Cell ◽

Cell Compartment ◽

Mhc I ◽

Mhc Ii ◽

Histocompatibility Complex ◽

Self Peptides

Transgenic mice expressing self major histocompatibility complex (MHC) class I (H-2Kb) antigen solely in lymphoid cell lineages do not acquire tolerance to H-2Kb expressed on skin grafts. H-2Kb-specific cytotoxic T cell responses were completely abrogated in these mice, even after they had rejected skin grafts. Moreover, thymocytes expressing T cell receptors that confer H-2Kb reactivity on cytotoxic CD8+ T cells were eliminated. The ability to reject grafts correlated with the presence of a novel population of H-2Kb-reactive CD4+ T cells. At least some of these CD4+ T cells recognize peptides derived from H-2Kb by processing. We conclude that self MHC I antigens induce tolerance in the CD8 T cell compartment via negative selection when expressed exclusively by lymphoid cells. In contrast, tolerance to MHC class II-restricted self peptides derived by processing of such MHC I antigens is not induced in the CD4 T cell compartment. This suggests that effective transfer of self antigens from lymphoid cells to MHC II-positive cells that can process and present them as self peptides to thymocytes or CD4+ T cells does not take place in vivo. Thus, sequestration of self antigens and MHC II molecules in distinct cell types in the thymic microenvironment allows potentially autoreactive and functionally competent CD4+ T cells that recognize cryptic MHC II-restricted self peptides to mature into the peripheral T cell repertoire under normal physiological circumstances.

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The Current Researches on T Follicular Helper Cells and Associated Diseases

Journal of Enam Medical College ◽

10.3329/jemc.v2i2.12843 ◽

2012 ◽

Vol 2 (2) ◽

pp. 85-91

Author(s):

Jianwei Zhou ◽

Cui Kong

Keyword(s):

T Cells ◽

T Cell ◽

Autoimmune Disease ◽

Infectious Diseases ◽

B Cell ◽

Humoral Immunity ◽

Cd4 T Cell ◽

T Follicular Helper Cells ◽

Tfh Cells ◽

Follicular Helper

T follicular helper (Tfh) cell is a new subpopulation of CD4+ T cell family, whose differentiation is affected by Bcl-6, Blimp-1, STAT3, STAT5 and so on, and it could affect or decide the development of other subsets of CD4+ T cells. The important function of Tfh cell is to help B cell mediate humoral immunity, many researches have proved that Tfh cells participate in the development of autoimmune disease, immunodeficient disease, tumor and infectious diseases. DOI: http://dx.doi.org/10.3329/jemc.v2i2.12843 J Enam Med Col 2012; 2(2): 85-91

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Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

10.1101/2020.08.06.236497 ◽

2020 ◽

Author(s):

Marco Künzli ◽

Peter Reuther ◽

Daniel D. Pinschewer ◽

Carolyn G. King

Keyword(s):

T Cells ◽

T Cell ◽

Viral Infection ◽

Cell Fate ◽

Cd4 T Cells ◽

Chronic Infection ◽

Signal Strength ◽

Cd4 T Cell ◽

Chronic Viral Infection ◽

Tfh Cells

AbstractA hallmark of the adaptive immune response is the ability of CD4 T cells to differentiate into a variety of pathogen appropriate and specialized effector subsets. A long-standing question in CD4 T cell biology is whether the strength of TCR signals can instruct one Th cell fate over another. The contribution of TCR signal strength to the development of Th1 and T follicular helper (Tfh) cells has been particularly difficult to resolve, with conflicting results reported in a variety of models. Although cumulative TCR signal strength can be modulated by the infection specific environment, whether or not TCR signal strength plays a dominant role in Th1 versus Tfh cell fate decisions across distinct infectious contexts is not known. Here we characterized the differentiation of CD4 TCR transgenic T cells responding to a panel of recombinant wild type or altered peptide ligand lymphocytic choriomeningitis viruses (LCMV) derived from acute and chronic parental strains. We found that while TCR signal strength positively regulates T cell expansion in both infection settings, it exerts opposite and hierarchical effects on the balance of Th1 and Tfh cells generated in response to acute versus persistent infection. The observation that weakly activated T cells, which comprise up to fifty percent of an endogenous CD4 T cell response, support the development of Th1 effectors highlights the possibility that they may resist functional inactivation during chronic infection. We anticipate that the panel of variant ligands and recombinant viruses described herein will be a valuable tool for immunologists investigating a wide range of CD4 T cell responses.Graphical abstractHighlightsIdentification of a wide panel of altered peptide ligands for the LCMV-derived GP61 peptideGeneration of LCMV variant strains to examine the impact of TCR signal strength on CD4 T cells responding during acute and chronic viral infectionThe relationship between TCR signal strength and Th1 differentiation shifts according to the infection context: TCR signal strength correlates positively with Th1 generation during acute infection but negatively during chronic infection.

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