scholarly journals The development of T and non-T cell lineages from CD34+ human thymic precursors can be traced by the differential expression of CD44.

1995 ◽  
Vol 181 (2) ◽  
pp. 475-483 ◽  
Author(s):  
C Márquez ◽  
C Trigueros ◽  
E Fernández ◽  
M L Toribio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Differential Expression ◽  
Intermediate Stage ◽  
Double Positive ◽  
Developmental Potential ◽  
Cell Lineages ◽  
Interleukin 7 ◽  
Cd34 Cells ◽  
Cd44 Upregulation

In addition to T-lineage cells, a small proportion of hematopoietic non-T cells are present in the human postnatal thymus. However, the origin of this minor non-T cell thymic compartment is presently unknown. In this study we have analyzed the developmental potential of the earliest human intrathymic precursors, characterized as CD34+ cells expressing intermediate levels of CD44. We show that these CD34+CD44int thymocytes cultured with interleukin 7 were able to develop simultaneously into both T- and non-T (monocytes and dendritic cells) -lineage cells. Both developmental pathways progress through a CD1+CD4+ intermediate stage, currently believed to be the immediate precursor of double positive thymocytes. However, separate progenitors for either T or non-T cells could be characterized within CD1+CD4+ thymocytes by their opposite expression of CD44. Downregulated levels of CD44 identified CD1+CD4+ T-lineage precursors, whereas CD44 upregulation occurred on CD1+CD4+ intermediates that later differentiated into non-T cells. Therefore, commitment of human early intrathymic precursors to either T or non-T cell lineages can be traced by the differential expression of the CD44 receptor.

β-Selection Is Associated With the Onset of CD8β Chain Expression on CD4+CD8+ Pre-T Cells During Human Intrathymic Development

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3491-3498 ◽  
Author(s):  
Yolanda R. Carrasco ◽  
César Trigueros ◽  
Almudena R. Ramiro ◽  
Virginia G. de Yébenes ◽  
Marı́a L. Toribio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Control Point ◽  
Intermediate Stage ◽  
Cell Receptor ◽  
Resting Cells ◽  
Double Positive ◽  
Human T Cell ◽  
A Minor

T-cell precursors that undergo productive rearrangements at the T-cell receptor (TCR) β locus are selected for proliferation and further maturation, before TCR expression, by signaling through a pre–TCR composed of the TCRβ chain paired with a pre–TCR (pT) chain. Such a critical developmental checkpoint, known as β-selection, results in progression from CD4−CD8− double negative (DN) to CD4+CD8+ double positive (DP) TCRβ−thymocytes. In contrast to mice, progression to the DP compartment occurs in humans via a CD4+ CD8−intermediate stage. Here we show that the CD4+CD8− to CD4+ CD8+ transition involves the sequential acquisition of the  and β chains of CD8 at distinct maturation stages. Our results indicate that CD8, but not CD8β, is expressed in vivo in a minor subset of DP TCRβ− thymocytes, referred to as CD4+CD8+ pre-T cells, mostly composed of resting cells lacking cytoplasmic TCRβ chain (TCRβic). In contrast, expression of CD8β heterodimers was selectively found on DP TCRβ− thymocytes that express TCRβicand are enriched for cycling cells. Interestingly, CD4+CD8+ pre-T cells are shown to be functional intermediates between CD4+ CD8−TCRβic− and CD4+CD8β+ TCRβic+thymocytes. More importantly, evidence is provided that onset of CD8β and TCRβic expression are coincident developmental events associated with acquisition of CD3 and pT chain on the cell surface. Therefore, we propose that the CD4+CD8+ to CD4+CD8β+ transition marks the key control point of pre-TCR–mediated β-selection in human T-cell development.

scholarly journals Evidence That γδ versus αβ T Cell Fate Determination Is Initiated Independently of T Cell Receptor Signaling

2001 ◽  
Vol 193 (6) ◽  
pp. 689-698 ◽  
Author(s):  
Joonsoo Kang ◽  
Ariane Volkmann ◽  
David H. Raulet
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Receptor ◽  
Gene Rearrangement ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Developmental Potential ◽  
Cd8 Cells ◽  
Interleukin 7

Two types of T cells, αβ and γδ, develop in vertebrates. How these two T cell lineages arise from a common thymic T progenitor is poorly understood. Differentiation of αβ lineage T cells requires the surrogate α chain (pTα), which associates with the T cell receptor (TCR) β chain to form the pre-TCR. γδ lineage development does not appear to involve an obligatory surrogate chain, but instead requires productive rearrangement and expression of both TCR γ and δ genes. It has been proposed that the quality of signals transmitted by the pre-TCR and γδ TCR are distinct and that these “instructive” signals determine the lineage fate of an uncommitted progenitor cell. Here we show that the thymic T progenitor cells (CD25+CD44+c-kit+CD3−CD4−CD8− thymocytes, termed pro-T cells) from young adult mice that have yet to express TCRs can be subdivided based on interleukin 7 receptor (IL-7R) expression. These subsets exhibit differential potential to develop into γδ versus αβ lineage (CD4+CD8+ cells) in the thymus. Upon intrathymic injection, IL-7Rneg-lo pro-T cells generated a 13-fold higher ratio of αβ lineage to γδ lineage cells than did IL-7R+ pro-T cells. Much of this difference was due to a fivefold greater potential of IL-7R+ pro-T cells to develop into TCR-γδ T cells. Evidence indicates that this biased developmental potential is not a result of enhanced TCR-γ gene rearrangement/expression in IL-7R+ pro-T cells. These results indicate that the pro-T cells are heterogeneous in developmental potential before TCR gene rearrangement and suggest that in some precursor cells the initial lineage commitment is independent of TCR-mediated signals.

scholarly journals Commitment of Immature CD4+8+ Thymocytes to the CD4 Lineage Requires CD3 Signaling but Does Not Require Expression of Clonotypic T Cell Receptor (TCR) Chains

1997 ◽  
Vol 186 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Harumi Suzuki ◽  
Yoichi Shinkai ◽  
Lawrence G. Granger ◽  
Frederick W. Alt ◽  
Paul E. Love ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
The Other ◽  
Double Positive ◽  
Cell Lineages

As a consequence of positive selection in the thymus, immature CD4+8+ double-positive, [DP] thymocytes selectively terminate synthesis of one coreceptor molecule and, as a result, differentiate into either CD4+ or CD8+ T cells. The decision by individual DP thymocytes to terminate synthesis of one or the other coreceptor molecule is referred to as lineage commitment. Previously, we reported that the intrathymic signals that induced commitment to the CD4 versus CD8 T cell lineages were markedly asymmetric. Notably, CD8 commitment appeared to require lineage-specific signals, whereas CD4 commitment appeared to occur in the absence of lineage-specific signals by default. Consequently, it was unclear whether CD4 commitment, as revealed by selective termination of CD8 coreceptor synthesis, occurred in all DP thymocytes, or whether CD4 commitment occurred only in T cell receptor (TCR)–CD3-signaled DP thymocytes. Here, we report that selective termination of CD8 coreceptor synthesis does not occur in DP thymocytes spontaneously. Rather, CD4 commitment in DP thymocytes requires signals transduced by either CD3 or ζ chains, which can signal CD4 commitment even in the absence of clonotypic TCR chains.

scholarly journals Transplantation of T Cell Depleted Haploidentical HSCT Following Non-Myeloablative (NMA) Conditioning: Combining the Power of Megadose Transplants with Post Transplant Cyclophosphamide (PTCY)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5765-5765
Author(s):  
Franco Aversa ◽  
Esther BacharLustig ◽  
Lucia Prezioso ◽  
Sabrina Bonomini ◽  
Noga Or Geva ◽  
...  
Keyword(s):  
T Cells ◽  
Renal Function ◽  
T Cell ◽  
High Risk ◽  
Immune Suppression ◽  
Post Transplant ◽  
Cell Lineages ◽  
Cd34 Cells ◽  
Donor Type ◽  
Autologous Hsct

Abstract The use of PTCY is associated with reduced risk for GVHD in T cell replete NMA haplo-human stem cell transplants (HSCT); however, this intervention is still not sufficiently safe to justify treatment of non-malignant diseases or as a platform for organ transplantation. Furthermore, use of immune suppression to ameliorate GVHD likely adversely impacts anti-tumor immunity. Conversely, risk of rejection after NMA conditioning presents a major challenge for graft survival in T cell depleted (TCD) haplo-HSCT. We now show in a total of 66 mice (9 experiments) that combining the power of megadose TCD HSCT with high dose PTCY (Fig.1A), enables marked and durable chimerism following NMA conditioning, while each modality alone was ineffective (Fig1B). Chimerism included all myeloid and lymphoid lineages, and LDA analysis of alloreactive T cells revealed specific immune tolerance towards donor stimulators (Fig.1C), also associated with acceptance of donor but not 3rd party skin. A similar protocol (Fig.2) was therefore developed for clinical use in patients with high risk hematologic malignancies. The first patient, a 54 yr old male with high-risk multiple myeloma (unfavorable cytogenetics, micromolecular disease and compromised renal function at diagnosis) was treated with 4 courses of Velcade-Thalidomide-Dexametasone and autologous HSCT, attaining complete remission with good performance status and normal renal function. Six months later, he received megadose (15.4 x106 CD34+ cells/kg) CD3/CD19 depleted (1.17 x105 CD3+T cells/kg) haloidentical PBPCs. Hematopoietic engraftment was achieved at day +15 with over 96% donor type chimerism during the first 6 months in the myeloid and B cell lineages. T cells during this period were predominantly of host type (10-23% donor type), gradually increasing to 63-72% at 9-12 months post transplant. EliSpot analysis of anti-donor CTLp revealed specific non-responsiveness. The patient overcame CMV (Fig.3A) and subsequently EBV reactivation without any treatment. Dextramer FACS analysis revealed that CMV specific CD8 T cells were exclusively of host origin (Fig3B-C). At 12 months, complete hematological remission and normal Free Light Chain ratio were confirmed. The second patient, a 50 yr old male with MM achieved a partial remission after 4 courses of Lenalidomide-Dexametasone. He subsequently underwent autologous HSCT, and was put on Lenalidomide maintenance until relapse after 3 yrs. Following 8 courses of Bortezomib-Dexametasone he achieved CR. The patient received a megadose (10.8 x106 CD34+ cells/kg) of CD3/CD19 depleted (1.2x105 CD3+T cells/kg) haploidentcal PBPCs. Despite transient engraftment (50% donor cell on day +17), graft failure with autologous recovery (0.04% donor-type chimerism) was documented on day +30. This may be due to the extended treatment (38 months) with lenalidomide, but rejection cannot be excluded. After 5 months, this patient tolerated a second haploidentical HSCT (different donor) after standard myeloablative conditioning (ATG, treosulfan, thiotepa and fludarabine) and alfa/beta TCR/CD19-depleted PBPCs. Two months since the second HSCT, he shows no sign of GvHD, very good immunological reconstitution, excellent quality of life, and remains in complete remission. Collectively, our murine proof of concept data supported by clinical experience in the first high risk MM patient, suggests that combining megadose TCD HSCT with PTCY can enable prompt and durable engraftment with almost complete chimerism in the myeloid and B cell lineages. The marked level of host T cells persisting during the first 6 months after HSCT can provide anti-viral immune protection until thymus-derived donor T cells are generated. Furthermore, our ability to avoid post transplant immune suppression with this GVHD-free protocol, thereby attaining robust anti-viral immunity, could also potentially offer enhanced GVL effect, valuable for high risk MM patients. The rejection experienced by the 2nd patient, although corrected by a 2nd myeloablative TCD HSCT, indicates that the conditioning must be fine-tuned to optimize engraftment in every patient.We are therefore testing, increasing TBI from 2Gy to 3Gy. Further studies will determine the efficacy of this approach in elderly MM patients, in non-malignant hematopoietic diseases, or as a prelude for organ transplantation and cell therapy. *F.A and E.B.L contributed equally Disclosures BacharLustig: Yeda LTD: Patents & Royalties. Or Geva:Yeda LTD: Patents & Royalties. Reisner:Cell Source LTD: Consultancy, Equity Ownership, Patents & Royalties, Research Funding.

scholarly journals The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells

2007 ◽  
Vol 204 (8) ◽  
pp. 1945-1957 ◽  
Author(s):  
Takeshi Egawa ◽  
Robert E. Tillman ◽  
Yoshinori Naoe ◽  
Ichiro Taniuchi ◽  
Dan R. Littman
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Cytotoxic T Cell ◽  
Thymocyte Development ◽  
Double Positive ◽  
Interleukin 7 ◽  
Genes Encoding ◽  
Single Positive

Members of the Runx family of transcriptional regulators are required for the appropriate expression of CD4 and CD8 at discrete stages of T cell development. The roles of these factors in other aspects of T cell development are unknown. We used a strategy to conditionally inactivate the genes encoding Runx1 or Runx3 at different stages of thymocyte development, demonstrating that Runx1 regulates the transitions of developing thymocytes from the CD4−CD8− double-negative stage to the CD4+CD8+ double-positive (DP) stage and from the DP stage to the mature single-positive stage. Runx1 and Runx3 deficiencies caused marked reductions in mature thymocytes and T cells of the CD4+ helper and CD8+ cytotoxic T cell lineages, respectively. Runx1-deficient CD4+ T cells had markedly reduced expression of the interleukin 7 receptor and exhibited shorter survival. In addition, inactivation of both Runx1 and Runx3 at the DP stages resulted in a severe block in development of CD8+ mature thymocytes. These results indicate that Runx proteins have important roles at multiple stages of T cell development and in the homeostasis of mature T cells.

scholarly journals Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Nature ◽  
2021 ◽  
Author(s):  
Justina X. Caushi ◽  
Jiajia Zhang ◽  
Zhicheng Ji ◽  
Ajay Vaghasia ◽  
Boyang Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
T Cell Receptors ◽  
Tumour Microenvironment ◽  
Lung Cancers ◽  
Cell Receptors ◽  
Interleukin 7

AbstractPD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

549 Characterizing double positive T cells in the tumor microenvironment: a tale of promiscuous cell fates

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A586-A586
Author(s):  
Sara Schad ◽  
Andrew Chow ◽  
Heng Pan ◽  
Levi Mangarin ◽  
Roberta Zappasodi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Human Melanoma ◽  
B16 Melanoma ◽  
T Cell Subsets ◽  
Double Positive ◽  
Cell Fates ◽  
Single Positive

BackgroundCD4 and CD8 T cells are genetically and functionally distinct cell subsets of the adaptive immune system that play pivotal roles in immune surveillance and disease control. During development in the thymus, transcription factors ThPOK and Runx3 regulate the differentiation and maturation of these two lineages into single positive T cells that enter the periphery with mutually exclusive expression of either the CD4 or CD8 co-receptor.1–2 Despite our expectation that these two cell fates are fixed, mature CD4+CD8+ double positive (DP) T cells have been described in the context of numerous immunological responses, including cancer, but their molecular and functional properties and therapeutic relevance remain controversial and largely unknown.3–5MethodsOur lab has identified and characterized a heterogenous DP T cell population in murine and human melanoma tumors comprised of CD4 and CD8 T cells re-expressing the opposite co-receptor and a parallel uptake in the opposite cell type’s phenotype and function. Using CD4 (Trp1) and CD8 (Pmel) transgenic TCR T cells specific to B16 melanoma antigens gp75 and gp100 respectively, we demonstrate the re-expression of the opposite co-receptor following adoptive T cell transfer in B16 melanoma tumor bearing mice.ResultsSpecifically, up to 50% of transferred CD4 Trp1 T cells will re-express CD8 to become a DP T cell in the tumor microenvironment. Further, these CD4 derived DP T cells upregulate CD8 lineage regulator Runx3 and cytolytic genes Gzmb, Gzmk, and Prf1 to become potent cytotoxic T cells. Alternatively, a subset of CD8 Pmel T cells differentiate into DP T cells characterized by the increased expression of CD4, ThPOK, and regulatory marker FoxP3 (figure 1). In addition, we utilized 10x single cell and ATAC sequencing to further characterize these divergent DP T cell populations among open repertoire T cells isolated from murine and human melanoma tumors.ConclusionsOur findings highlight the capability of single positive T cells to differentiate in response to antigen and local stimuli into novel T cell subsets with polyfunctional characteristics. The resulting cell subsets will potentially affect the tumor microenvironment in distinct ways. Our studies may inform therapeutic approaches to identify antigen specific T cells as well as innovative signaling pathways to target when genetically engineering T cells to optimize cytotoxic function in the setting of adoptive cell therapy.Ethics ApprovalThe human biospecimen analyses were approved by Memorial Sloan Kettering Cancer Center IRB #06-107ReferencesEllmeier W, Haust L & Tschismarov R. Transcriptional control of CD4 and CD8 coreceptor expression during T cell development. Cell Mol Life Sci 2013;70:4537–4553.Luckey MA, et al. The transcription factor ThPOK suppresses Runx3 and imposes CD4+ lineage fate by inducing the SOCS suppressors of cytokine signaling. Nature Immunology 2014; 15, 638–645.Bohner P, et al. Double positive CD4(+)CD8(+) T Cells are enriched in urological cancers and favor T Helper-2 polarization. Front Immunol 2019; 10, 622.Nascimbeni M, Shin E-C, Chiriboga L, Kleiner DE & Rehermann B. Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions. Blood 2004;104:478–486.Nishida K, et al. Clinical importance of the expression of CD4+CD8+ T cells in renal cell carcinoma. Int Immunol 2020;32:347–357.

scholarly journals Evidence for the divergence of innate and adaptive T-cell precursors before commitment to the αβ and γδ lineages

Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6591-6600 ◽  
Author(s):  
Jan Kisielow ◽  
Luigi Tortola ◽  
Jacqueline Weber ◽  
Klaus Karjalainen ◽  
Manfred Kopf
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Negative Selection ◽  
Intraepithelial Lymphocytes ◽  
Lineage Commitment ◽  
Γδt Cells ◽  
Cell Lineages ◽  
Innate T Cells ◽  
Tcr Signals

Abstract In addition to adaptive T cells, the thymus supports the development of unconventional T cells such as natural killer T (NKT) and CD8αα intraepithelial lymphocytes (IELs), which have innate functional properties, particular antigenic specificities, and tissue localization. Both conventional and innate T cells are believed to develop from common precursors undergoing instructive, TCR-mediated lineage fate decisions, but innate T cells are proposed to undergo positive instead of negative selection in response to agonistic TCR signals. In the present study, we show that, in contrast to conventional αβT cells, innate αβT cells are not selected against functional TCRγ rearrangements and express TCRγ mRNA. Likewise, in contrast to the majority of γδT cells, thymic innate γδT cells are not efficiently selected against functional TCRβ chains. In precursors of conventional T cells, autonomous TCR signals emanating from the pre-TCR or γδTCR in the absence of ligand mediate selection against the TCR of the opposite isotype and αβ/γδ lineage commitment. Our data suggest that developing innate T cells ignore such signals and rely solely on agonistic TCR interactions. Consistently, most innate T cells reacted strongly against autologous thymocytes. These results suggest that innate and adaptive T-cell lineages do not develop from the same pool of precursors and potentially diverge before αβ/γδ lineage commitment.

Altered thymocyte and T cell development in neonatal mice with hyperoxia-induced lung injury

2018 ◽  
Vol 46 (4) ◽  
pp. 441-449
Author(s):  
Sowmya Angusamy ◽  
Tamer Mansour ◽  
Mohammed Abdulmageed ◽  
Rachel Han ◽  
Brian C. Schutte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Injury ◽  
T Cell Development ◽  
Adaptive Immune System ◽  
Cell Development ◽  
Thymocyte Development ◽  
Double Positive ◽  
Neonatal Mice ◽  
Single Positive

Abstract Background: The adaptive immune system of neonates is relatively underdeveloped. The thymus is an essential organ for adaptive T cell development and might be affected during the natural course of oxygen induced lung injury. The effect of prolonged hyperoxia on the thymus, thymocyte and T cell development, and its proliferation has not been studied extensively. Methods: Neonatal mice were exposed to 85% oxygen (hyperoxia) or room air (normoxia) up to 28 days. Flow cytometry using surface markers were used to assay for thymocyte development and proliferation. Results: Mice exposed to prolonged hyperoxia had evidence of lung injury associated alveolar simplification, a significantly lower mean weight, smaller thymic size, lower mean thymocyte count and higher percentage of apoptotic thymocytes. T cells subpopulation in the thymus showed a significant reduction in the count and proliferation of double positive and double negative T cells. There was a significant reduction in the count and proliferation of single positive CD4+ and CD8+ T cells. Conclusions: Prolonged hyperoxia in neonatal mice adversely affected thymic size, thymocyte count and altered the distribution of T cells sub-populations. These results are consistent with the hypothesis that prolonged hyperoxia causes defective development of T cells in the thymus.

scholarly journals Interleukin 7 Increases Human Immunodeficiency Virus Type 1 LAI-Mediated Fas-Induced T-Cell Death

2005 ◽  
Vol 79 (5) ◽  
pp. 3195-3199 ◽  
Author(s):  
Jean-Daniel Lelièvre ◽  
Frédéric Petit ◽  
Damien Arnoult ◽  
Jean-Claude Ameisen ◽  
Jérôme Estaquier
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Infection ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Fas-mediated T-cell death is known to occur during human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 LAI (HIV-1LAI) primes CD8+ T cells from healthy donors for apoptosis, which occurs after Fas ligation. This effect is counteracted by a broad caspase inhibitor (zVAD-fmk). Fas-mediated cell death does not depend on CD8+ T-cell infection, because it occurred in the presence of reverse transcriptase inhibitors. However, purified CD8+ T cells are sensitive to Fas only in the presence of soluble CD4. Finally, we found that interleukin 7 (IL-7) increases Fas-mediated CD4+ and CD8+ T-cell death induced by HIV-1LAI. Since high levels of IL-7 are a marker of poor prognosis during HIV infection, our data suggest that enhancement of Fas-mediated T-cell death by HIV-1LAI and IL-7 is one of the mechanisms involved in progression to AIDS.

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