Th2.rapa Cell Treatment of Established Murine Acute GVHD Is Abrogated by IL-2 Therapy and T Regulatory Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2169-2169
Author(s):  
Jason E. Foley ◽  
Jacopo Mariotti ◽  
Shoba Amarnath ◽  
Soo Han ◽  
Michael Eckhaus ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Treg Cell ◽  
Treg Cells ◽  
Th2 Cells ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Cell Product ◽  
Cell Responses ◽  
Th2 Cell ◽  
Ifn Γ

Abstract Rapamycin-generated donor Th2 cells attenuate established acute murine GVHD (Foley et al, JI, 2005) and are dependent in part upon IL-4 and IL-10 secretion (ASBMT Meeting, 2007). That is, Th2.rapa cell recipients (Th2 infusion, d 14 post-BMT) had increased survival relative to GVHD controls (post-BMT survival, median days; 33.7±0.4 vs. 24.8±1.2; p=0.0002) whereas recipients of IL-4 or IL-10 knockout Th2.rapa cells did not have increased survival (28.9±0.3 and 24.6±0.2 days, respectively; p=NS). These data indicate that Th2.rapa cells operate through a Th2-type mechanism rather than a Treg cell mechanism; in addition, we found that Th2.rapa cells expressed low levels of the Treg cell transcription factor, Foxp3 (<5% CD4+Foxp3+). Additional experiments were performed to further investigate a potential role of Treg cell biology to Th2.rapa cell therapy. First, we hypothesized that IL-2 therapy may promote Th2.rapa cell expansion and efficacy in a manner analogous to IL-2 promotion of Treg cell responses in vivo. Second, we hypothesized that enrichment of the Th2.rapa cell product with natural (unmanipulated) Treg cells may enhance an anti-GVHD effect. Contrary to our first hypothesis, we found that IL-2 therapy (50,000 IU bid; d14–18 post-BMT) reduced the number of splenic Th2.rapa cells at d 19 post-BMT (CD90.1-marked cells, million [M]/spleen; 5.0±0.4 [no IL-2] vs. 2.3±0.4 [+IL-2]; p=<0.001) and increased the number of unmanipulated donor CD4+ cells (CD45.2-marked cells, M/spleen; 16.6±0.7 [no IL-2] vs. 26.6±2.4 [+IL-2]; p=0.004) and CD8+ cells (15.9±1.7 [no IL-2] vs. 23.9±2.4 [+IL-2]; p=0.03). IL-2 therapy also inhibited Th2.rapa cell-mediated cytokine polarization (d 19 post-BMT, pg/ml; IL-4 reduced from 3501±179 [no IL-2] to 1116±261 [+IL-2], p=<0.0001; IL-10 reduced from 707±56 [no IL-2] to 288±37 [+IL-2], p=0.0002; and IFN-γ increased from 81±22 [no IL-2] to 320±97 [+IL-2], p=0.042). Importantly, for Th2.rapa cell recipients, IL-2 therapy reduced post-BMT survival (d post-BMT; 42.0±0.5 [no IL-2] vs. 33.8±1.0 [+IL-2], p=<0.0001). With regard to our second hypothesis, we found that addition of Treg cells to the Th2.rapa cell product (Treg to Th2.rapa cell ratio, 1:10) reduced the number of Th2.rapa cells at d 19 post-BMT (M/spleen; 16.6±1.3 [no Treg] vs. 7.9±1.2 [+ Treg], p=0.0012) and increased the number of unmanipulated donor CD4+ cells (M/spleen; 12.4±0.7 [no Treg] vs. 20.7±0.8 [+Treg], p=<0.0001) and CD8+ cells (M/spleen; 8.4±0.8 [no Treg] vs. 16.1±1.4 [+Treg], p= 0.0014). Treg cell co-infusion also inhibited Th2.rapa cell-mediated cytokine polarization (d 19 post-BMT, pg/ml; IL-4 reduced from 497±47 [no Treg] to 100±15 [+ Treg]; p=<0.0001); IL-10 reduced from 160±32 [no Treg] to 27±7 [+Treg]; p= 0.004; and IFN-γ increased from 83±5 [no Treg] to 230±40 [+Treg]; p=0.006). Finally, for Th2.rapa cell recipients, co-infusion of Treg cells reduced post-BMT survival (median d post-BMT; 44.2±1.1 [no Treg] vs. 30.7±1.3 [+Treg]; p=0.0002). In conclusion, interventions that promote Treg cell responses, namely infusion of IL-2 and co-administration of natural Treg cells, reduce Th2.rapa cell promotion of IL-4 and IL-10 post-BMT and reduce the Th2 cell-mediated survival advantage against established GVHD. Because IL-4 and IL-10 are required for Th2.rapa cell therapy of GVHD in this model, these new data indicate that Treg cells abrogate Th2.rapa cell therapy by inhibiting the Th2 cell effector response.

scholarly journals PD-L1 – PD-1 interactions limit effector Treg cell populations at homeostasis and during infection

2020 ◽  
Author(s):  
J.A. Perry ◽  
J.T. Clark ◽  
J. Gullicksrud ◽  
J. DeLong ◽  
L. Shallberg ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cell ◽  
Cell Activity ◽  
T Cell Responses ◽  
Treg Cells ◽  
Whole Body ◽  
Cell Responses ◽  
Early Production ◽  
Ifn Γ ◽  
Specific Deletion

AbstractWhile much is known about the factors that promote the development of diverse Treg cell responses, less is known about the pathways that constrain Treg cell activities. The studies presented here reveal that at homeostasis there is a population of effector Treg cells that express PD-1, and that blockade of PD-L1 or loss of PD-1 results in increased Treg cell activity. In response to infection with the parasite T. gondii, the early production of IFN-γ results in widespread upregulation of PD-L1. Moreover, blockade of PD-L1, whole body deletion of PD-1, or lineage-specific deletion of PD-1 in Foxp3+ cells prevented the loss of the effector Treg cells but resulted in reduced pathogen specific CD4+ T cell responses during infection. Thus, at homeostasis basal PD-L1 expression constrains and tunes the pool of Treg cells, but during infection the upregulation of PD-L1 provides a mechanism to contract the Treg cell population required to maximize the development of pathogen specific CD4+ T cell responses.

Prevention of Rat Cardiac Allograft Rejection by Host Th2 Cell Adoptive Transfer

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 365-365
Author(s):  
Shoba Amarnath ◽  
Hao Chen ◽  
Carliann M Costanzo ◽  
Joanna M Swerczek ◽  
Michael A Solomon ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Cd8 T Cells ◽  
Allograft Rejection ◽  
Ex Vivo ◽  
Cardiac Allograft ◽  
Th2 Cells ◽  
Cell Transfer ◽  
Th2 Cell ◽  
Ifn Γ

Abstract We have recently shown that ex vivo manufactured, rapamycin-resistant donor Th2 cells (Th2.R cells) prevent the rejection of allogeneic bone marrow grafts through a process that involves IL-4-mediated polarization of host T cells towards a Th2 phenotype. Because donor T cell therapy lacks feasibility in the setting of cardiac allograft transplantation using cadaveric donors, we developed an approach to prevent rejection that incorporates host Th2 cell therapy prior to organ transplantation. The aims of the study were to: (1) develop a method for the ex vivo manufacture of rat Th2.R cells and inject such syngeneic Th2.R cells just prior to class I and class II disparate cardiac allografting; (2) determine whether such adoptive host Th2.R cell transfer polarizes post-transplant immunity towards a Th2 phenotype; and (3) evaluate in a preliminary manner whether Th2.R cell transfer reduces graft rejection in a model that uses sub-optimal cyclosporine therapy. Recipient-type (Black Norway, BN) CD4+ T cells were co-stimulated with anti-rat anti-CD3 and –CD28 antibodies in the presence of rapamycin, rrIL4, rhuIL-2, and rhIL7 (3-day culture interval). The Th2.R cell cytokine phenotype was determined by intra-cellular flow cytometry and multi-analyte testing of supernatants obtained after repeat co-stimulation. Th2.R cells were injected (i.v.; 1 × 107 cells) 2–3 hours prior to cardiac allografting (donor strain, Dark Agouti; DA). Cardiac function was evaluated clinically by cardiac palpation through day 28 post-grafting. At day 28, histology studies and immune function studies were performed, including assessment of host-anti-donor alloreactivity. Engraftment controls (cohort #1) and rejection controls (cohort #2) received cyclosporine (CSA) through the full 28 days or only through day 18, respectively; the experimental cohort (#3) received host Th2.R cells followed by the short-course of CSA. Supernatants from the Th2.R cell product contained 1500 pg/ml IL-4 and only 50 pg/ml of IFN-γ; the frequency of IL-4+ cells and IFN-γ+ cells was 10% and 1%, respectively. Clinical rejection was observed in cohort #2 (3/3 subjects) whereas all subjects in cohorts #1 and #3 had full cardiac function through day 28 (cohort #1- 2/3 subjects; cohort #3- 3/3 subjects). Relative to rejection controls, Th2.R cell recipients had a reduced frequency of intra-cardiac CD8+ T cells (%CD8+ T cells, 9.2 ± 6.2 vs. 1.1 ± 0.3; p&lt;0.001) and spleen CD8+ T cells (1.9 ± 0.2 vs. 0.5 ± 0.2; p=0.014). Furthermore, after ex vivo re-stimulation with donor-type dendritic cells, intra-cardiac CD8+ T cells from Th2.R cell recipients tended to produce less IFN-γ relative to rejection controls (pg/ml in supernatant; 15.7 ± 1.4 vs. 44.2 ± 1.4; p=0.07) and tended to produce increased IL-4 relative to rejection controls (1974 ± 140 vs. 260 ± 291; p=0.07). This study demonstrates a feasible and successful methodology for inducing recipient based immunotolerance by generating rapamycin-resistant Th2 cells in the rat species.. Adoptive transfer of host-type Th2.R cells just prior to fully genetically-disparate cardiac allograft transplantation results in a shift towards Th2 cytokines post-transplant, a reduction in the frequency of intra-cardiac T cell infiltration, and shows promise as a novel method to prevent cardiac allograft rejection.

scholarly journals The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Agnieszka M Kabat ◽  
Oliver J Harrison ◽  
Thomas Riffelmacher ◽  
Amin E Moghaddam ◽  
Claire F Pearson ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Treg Cells ◽  
Th2 Cells ◽  
Metabolic Adaptation ◽  
Cell Responses ◽  
Th2 Cell ◽  
Autophagy Gene ◽  
Th Cell ◽  
Inflammatory Bowel

A polymorphism in the autophagy gene Atg16l1 is associated with susceptibility to inflammatory bowel disease (IBD); however, it remains unclear how autophagy contributes to intestinal immune homeostasis. Here, we demonstrate that autophagy is essential for maintenance of balanced CD4+ T cell responses in the intestine. Selective deletion of Atg16l1 in T cells in mice resulted in spontaneous intestinal inflammation that was characterized by aberrant type 2 responses to dietary and microbiota antigens, and by a loss of Foxp3+ Treg cells. Specific ablation of Atg16l1 in Foxp3+ Treg cells in mice demonstrated that autophagy directly promotes their survival and metabolic adaptation in the intestine. Moreover, we also identify an unexpected role for autophagy in directly limiting mucosal TH2 cell expansion. These findings provide new insights into the reciprocal control of distinct intestinal TH cell responses by autophagy, with important implications for understanding and treatment of chronic inflammatory disorders.

scholarly journals Schistosoma mansoni Larvae Do Not Expand or Activate Foxp3+Regulatory T Cells during Their Migratory Phase

2015 ◽  
Vol 83 (10) ◽  
pp. 3881-3889 ◽  
Author(s):  
Stephen A. Redpath ◽  
Nienke van der Werf ◽  
Andrew S. MacDonald ◽  
Rick M. Maizels ◽  
Matthew D. Taylor
Keyword(s):  
Schistosoma Mansoni ◽  
Treg Cell ◽  
Interleukin 10 ◽  
Treg Cells ◽  
Th2 Cells ◽  
Parasitic Helminth ◽  
Content Type ◽  
Cell Responses ◽  
Helminth Infections ◽  
Suppressive Cytokine

Foxp3+regulatory T (Treg) cells play a key role in suppression of immune responses during parasitic helminth infection, both by controlling damaging immunopathology and by inhibiting protective immunity. During the patent phase ofSchistosoma mansoniinfection, Foxp3+Treg cells are activated and suppress egg-elicited Th2 responses, but little is known of their induction and role during the early prepatent larval stage of infection. We quantified Foxp3+Treg cell responses during the first 3 weeks of murineS. mansoniinfection in C57BL/6 mice, a time when larval parasites migrate from the skin and transit the lungs en route to the hepatic and mesenteric vasculature. In contrast to other helminth infections,S. mansonidid not elicit a Foxp3+Treg cell response during this early phase of infection. We found that the numbers and proportions of Foxp3+Treg cells remained unchanged in the lungs, draining lymph nodes, and spleens of infected mice. There was no increase in the activation status of Foxp3+Treg cells upon infection as assessed by their expression of CD25, Foxp3, and Helios. Furthermore, infection failed to induce Foxp3+Treg cells to produce the suppressive cytokine interleukin 10 (IL-10). Instead, only CD4+Foxp3−IL-4+Th2 cells showed increased IL-10 production upon infection. These data indicate that Foxp3+Treg cells do not play a prominent role in regulating immunity toS. mansonilarvae and that the character of the initial immune response invoked byS. mansoniparasites contrasts with the responses to other parasitic helminth infections that promote rapid Foxp3+Treg cell responses.

scholarly journals Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 38 ◽  
Author(s):  
Azza Abdel-Gadir ◽  
Amir H. Massoud ◽  
Talal A. Chatila
Keyword(s):  
Immune Responses ◽  
Treg Cell ◽  
Allergic Diseases ◽  
Treg Cells ◽  
Immunological Tolerance ◽  
Inflammatory Disorders ◽  
Cell Responses ◽  
Recent Advances ◽  
And Function ◽  
Is Failure

Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders.

scholarly journals T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

2016 ◽  
Vol 113 (5) ◽  
pp. E568-E576 ◽  
Author(s):  
Jimena Perez-Lloret ◽  
Isobel S. Okoye ◽  
Riccardo Guidi ◽  
Yashaswini Kannan ◽  
Stephanie M. Coomes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Allergic Diseases ◽  
Treg Cells ◽  
Th2 Cells ◽  
T Helper 2 ◽  
Cytokines And Chemokines ◽  
Th2 Cell

There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ+CD4+ T-helper 2 (TH2) cells orchestrate the type-2–driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081–E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4gfp+αβ+CD4+ TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell–intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24−/− T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1–regulated signaling. Following this prediction, we found that Trim24−/− T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β–mediated activation in vitro and in vivo, and fail to respond to IL-1β–exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell–intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.

scholarly journals Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Kun He ◽  
Angela Hettinga ◽  
Sagar Laxman Kale ◽  
Sanmei Hu ◽  
Markus M. Xie ◽  
...  
Keyword(s):  
Allergic Airway Inflammation ◽  
Cell Development ◽  
Th2 Cells ◽  
Th2 Response ◽  
Cell Responses ◽  
Th2 Cell ◽  
Th2 Immune Response ◽  
Upstream Promoter ◽  
Gata3 Expression ◽  
Anti Inflammatory Cytokine

A Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung to inhaled but not systemically delivered allergens but is dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, leading to increased GATA3 expression in lung Th2 cells. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to up-regulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10–STAT3–Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.

scholarly journals Selective Expression and Functions of Interleukin 18 Receptor on T Helper (Th) Type 1 but not Th2 Cells

1998 ◽  
Vol 188 (8) ◽  
pp. 1485-1492 ◽  
Author(s):  
Damo Xu ◽  
Woon Ling Chan ◽  
Bernard P. Leung ◽  
David Hunter ◽  
Kerstin Schulz ◽  
...  
Keyword(s):  
Th2 Cells ◽  
Interleukin 18 ◽  
T Helper ◽  
Th2 Cell ◽  
A Cell ◽  
Ifn Γ

Interleukin (IL)-18 induces interferon (IFN)-γ synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rβ2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R–derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin–T cell antigen receptor-αβ transgenic mice (D011.10). Anti–IL-18R antibody inhibited IL-18– induced IFN-γ production by Th1 clones in vitro. In vivo, anti–IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-γ and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

scholarly journals Blimp-1 is essential for Th2 cell development and allergic asthma

2019 ◽  
Author(s):  
Kun He ◽  
Angela Hettinga ◽  
Sagar Laxman Kale ◽  
Sanmei Hu ◽  
Markus M. Xie ◽  
...  
Keyword(s):  
Transcriptional Repressor ◽  
Allergic Airway Inflammation ◽  
Cell Development ◽  
Th2 Cells ◽  
Th2 Response ◽  
Cell Responses ◽  
Th2 Cell ◽  
Th2 Immune Response ◽  
Upstream Promoter ◽  
Gata3 Expression

AbstractA Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung, but dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, which is necessary to drive GATA3 expression. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to upregulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10-STAT3-Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.SummaryThe transcriptional repressor Blimp-1 acts via a pro-inflammatory IL-10-STAT3 axis as a critical positive regulator of Th2 cells in the lung in response to allergens driving pathophysiology associated with asthma disease.

Persistence of High Viral Load Abrogates Long-Term HIV-Specific Memory CD4 T-Cells Producing Interleukin-2.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3104-3104
Author(s):  
Mohamed-Rachid Boulassel ◽  
Souheil-Antoine Younes ◽  
Bader Yacine-Diab ◽  
Rafick-Pierre Sekaly ◽  
Jean Pierre Routy
Keyword(s):  
Viral Load ◽  
Long Term Memory ◽  
Memory Cells ◽  
Cd4 Cells ◽  
Proliferating Cells ◽  
Term Memory ◽  
Cell Responses ◽  
Specific Memory ◽  
Ifn Γ

Abstract Virus-specific CD4 T-cells are believed to play a critical role in determining the persistence of memory and effector CD8 T-cell responses during viral infections. However, the reasons for which human immunodeficiency virus (HIV)-specific CD4 cells fail to generate effective CD8 cell responses remain incompletely understood. In this study, we analyzed the HIV-specific CD4 cells in 10 aviremic (viral load &lt; 50 copies/ml) and 8 viremic (mean viral load 45,295 copies/ml) patients treated during primary HIV infection and followed for up to 6 years. At the time of apheresis, median CD4 T cell counts for aviremic and viremic patients were 671 cells/μl and 485 cells/μl respectively. Using Gag and Nef overlapping HIV peptides, the highly sensitive CFSE-based proliferation assay and intracellular staining techniques, we observed that proliferative Gag and Nef peptide-specific CD4 cell responses were 30-fold higher in aviremic patients compared to viremic. Several subsets of HIV-specific memory CD4 cells endowed with different proliferative and functional capacities were identified. We observed two subsets of HIV-specific memory CD4 cells in aviremic patients, CD45RA− CCR7+ central memory cells (Tcm) producing exclusively IL-2 and CD45RA− CCR7− effector memory cells (Tem) that produced both IL-2 and IFN-γ. In contrast, in viremic patients, Tem were found to unexpectedly produce IFN-γ exclusively. Longitudinal data showed that only cells, which were capable of producing IL-2, persisted as long-term memory cells. In viremic patients, HIV-specific CD4 cells that produce INF-γ were found only during periods of elevated viral loads. To test if the presence of IL-2 could restore the proliferation of these cells, we stimulated CD4 cells from viremic patients with a pool of peptides, which gave strong IFN-γ responses in these patients in the presence of exogenous IL-2. The addition of IL-2 during the in vitro peptide stimulation dramatically increased the fraction of proliferating cells. This experiment strongly suggests that the impaired proliferation of CD4 cells from viremic patients is not caused by a virus-mediated destruction of proliferating cells but a lack of producing IL-2. Altogether, these results indicate that long-term memory HIV-specific CD4 cell produce mainly IL-2, while those producing IFN-γ are short-lived. These findings favor a model in which Tcm are continuously produced in limited numbers but under continuous viral stimulation are rapidly induced to differentiate into IFN-γ only-producing cells that lack the capacity for self-renewal.These findings also indicate that treatment strategies aimed to increase the long-term memory CD4 cells are needed for future HIV vaccine development.

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