Programmed Death 1 Regulates Memory Phenotype CD4 T Cell Accumulation, Inhibits Expansion of the Effector Memory Phenotype Subset and Modulates Production of Effector Cytokines

54 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95% CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.

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Programmed-death receptor (PD-1) and its role in T cell biology

10.12681/eadd/38208 ◽

2013 ◽

Author(s):

Joanna-Jean Charlton

Keyword(s):

T Cell ◽

Cell Biology ◽

Death Receptor ◽

Effector Memory ◽

Programmed Death ◽

T Cell Biology ◽

Programmed Death 1

Tα Τ λεμφοκύτταρα που εμφανιζουν φαινότυπο κυττάρων μνήμης (ΜemoryPhenotype-MP) και απαντώνται σε μη ανοσοποιημένους ποντικούς,έχουν λειτουργικάχαρακτηριστικά κλασικών κυττάρων μνήμης και παρέχουν προστασία έναντι μολύνσεωνπαίζοντας ρόλο τόσο στήν εγγενή όσο και στήν επίκτητη ανοσία. Οι μηχανισμοί πουδιέπουν την ομοιόσταση αυτών των κυττάρων παραμένουν ασαφείς.Στη διδακτορικήαυτή διατριβή αποκαλύψαμε ένα κρίσιμο ρόλο που παίζει ο αρνητικόςσυνενεργοποιητής Programmed Death 1 (PD-1) στήν εξελικτική τύχη αυτών των MPκυττάρων. Στα λεμφικά όργανα και ιστούς ποντικών, στούς οποίους έχει απαλειφθεί γενετικάτο γονίδιο PD-1 (PD-1KO ποντίκια), παρατηρείται μιά σημαντική συσσώρευσηλειτουργικών MP CD8 T λεμφοκυττάρων και συγκεκριμένα δραστικών λεμφοκυττάρωνμνήμης(T Effector Memory-TEM).Αυτά τα κύτταρα έχουν μειωμένη ικανότηταπολλαπλασιασμού αλλά αυξημένη δυνατότητα επιβίωσης σε σχέση με του αγρίου τύπου.Επίσης παράγουν δραστικά μόρια μετά απο έκθεση σε εστέρες φορβόλης ή ενδογενήερεθίσματα. Παρομοίως κατά τον πολλαπλασιασμό τών παρθένων CD8 κυττάρων πουέπεται μιάς λεμφοπενίας, μια κατάσταση που οδηγεί σε εμφάνιση Τ λεμφοκυττάρων τύπουμνήμης, παρατηρείται μετάπτωσή τους κυρίως σε TEM στα PD-1 KO ποντίκια. Η υιοθέτησηαυτού του φαινότυπου αποτελεί ένα γεγονός συνυφασμένο με τον γονότυπο μόνο τώνCD8 T λεμφοκυττάρων και αποδείχθηκε με πειράματα χιμαιρισμού. Επιπρόσθετα κύτταρακεντρικής μνήμης (TCM) από PD-1 KO ποντίκια που μεταφέρθηκαν σε νέους ιστολογικάσυμβατούς αποδέκτες μετέπεσαν στη συντριπτική πλειοψηφία τους σε κύτταρα δραστικήςμνήμης (TEM) ενώ το αντίστροφο αφορούσε ένα πολύ μικρό ποσοστό των μεταφερθέντωνκυττάρων. Από τα παραπάνω και από τα αποτελέσματα τής μεταγραφικής ανάλυσηςολόκληρου του μεταγραφώματος τών CD8 TCM κυττάρων καταλήγουμε στο συμπέρασμα ότιτο μόριο PD-1 παίζει καθοριστικό ρόλο στη διαμόρφωση τών υποτύπων τών κυττάρωνμνήμης.

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Faculty Opinions recommendation of Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses.

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

10.3410/f.1088493.541560 ◽

2007 ◽

Author(s):

P'ng Loke

Keyword(s):

T Cell ◽

Costimulatory Molecule ◽

T Cell Responses ◽

Cell Responses ◽

Programmed Death ◽

Programmed Death 1

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Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis

Journal of Fungi ◽

10.3390/jof5030063 ◽

2019 ◽

Vol 5 (3) ◽

pp. 63

Author(s):

Alice Bayiyana ◽

Samuel Okurut ◽

Rose Nabatanzi ◽

Godfrey Zziwa ◽

David R. Boulware ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Cell Surface ◽

Cd8 T Cells ◽

Cryptococcal Meningitis ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Effector Memory ◽

Memory Subset

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.

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