UvA-DARE (Digital Academic Repository) Contributions of CD27 and relatives to the specific immune response Hendriks, J.A. Publication date 2004 Link to publication Citation for published version (APA): Hendriks, J. A. (2004). Contributions of CD27 and relatives to the specific immune response. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:04 Oct 2021 Chapter 6 OX40 and 4-1BB, together with CD27, determine the amount of CD8+ memory T cells formed and imprint into them the capacity for secondary expansion. Jenny Hendriks, Yanling Xiao, Kazuo Sugumura, Naoto Ishii and Jannie Borst Submitted 79 80 OX40, 4-1 BB andCD27 shape CD8+ T cell memory OX40 and 4-1BB, together with CD27, determine the amount of CD8+ memory T cells formed and imprint into them the capacity for secondary expansion. Jenny Hendriks1, Yanling Xiao', Kazuo Sugumura2, Naoto Ishii2 and Jannie Borst1'3 'Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands, department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. Summary We have established the relative impact of CD27-, OX40- and 4-1BB receptor/ligand interactions on the CD8+ T cell response to influenza virus. CD27 and to a lesser extent 4-1BB promoted accumulation of CD8+ effector T cells during primary infection, while OX40 did not. Nevertheless, all three receptor/ligand systems equally and critically contributed to the formation of memory CD8+ T cells. Moreover, they collectively determined the magnitude of effector CD8+ T cell accumulation after secondary infection. Surprisingly, wild-type CD8+ memory T cells did not require stimulation by OX40- or 4-1BB ligand throughout the secondary response. However, they were impaired in maintenance and capacity for secondary expansion, when they had been generated in OX40- or 4-1BB ligand-deficient mice. Thus, stimulation of CD8+ T cells during the primary response by OX40- and 4-1BB ligand presented on non-T cells endows them with the capacity for long-term survival and imprints their potential for secondary expansion. Introduction An effective immune response relies on the clonal amplification of antigen-specific T cells and their accumulation at the site of infection. For long-term protection, part of the antigen- specific T cell pool must be retained as memory cells, which respond rapidly to renewed challenge. Naive T cell expansion is initiated by TCR signaling, but this alone is not sufficient. Costimulatory receptors must be engaged, which promote T cell division and survival and may direct development of effector functions. Costimulatory receptors comprise immunoglobulin superfamily members, including CD28 and ICOS, and TNF receptor family members, such as CD27, OX40 and 4-IBB (Watts and DeBenedette, 1999; Croft, 2003). Like the TCR, CD28 and relatives signal via tyrosine kinases, while costimulatory TNF receptor family members signal via TRAF adaptors (Gravestein and Borst, 1998). Both mechanisms activate the NFKB and Jun kinase pathways, posing the 81 Chapter 6 question whether signals provided by the various costimulatory receptors merely add to TCR signaling and to each other in quantitative terms. Previously, we have determined that CD27 gives a critical survival signal to activated T cells (Hendriks et al., 2003). Upon intranasal infection with influenza virus, CD27 and CD28 equally contributed to expansion of virus-specific T cells and their accumulation at the effector site. CD27 and CD28 appeared complementary in qualitive terms, i.e. CD27 did not promote Cell division, as well as in the timing of their pro-survival effects. Like CD28 (Okkenhaug et al, 2001), CD27 probably counters apoptosis by transcriptionally upregulating inhibitory Bcl-2 family members (Van Oosterwijk and Van Lier, pers. comm.). OX40 and 4-IBB, the closest relatives of CD27 (Croft, 2003),also promote activated T cell survival by stimulating expression of anti-apoptotic Bcl-2 family members, such as Bcl-xL and Bfl-1 (Rogers et al., 2001; Lee et al., 2002). While this mechanism of action suggests redundancy between CD27, OX40 and 4-IBB, complementarity may lie in the timing of their involvement in the T cell response. The expression patterns of these receptors give a clue that this might be the case. CD27 is expressed on naive, effector and memory T cells (Lens et al., 1998; Gravestein et al., 1995), but OX40 and 4-IBB are acquired at the effector stage. They are induced by TCR signals, with CD28 enhancing the kinetics and levels of expression (Al-Shamkani et al., 1996; Gramaglia et al., 1998; Rogers et al., 2001; Pollok et al., 1993). Accordingly, in activated T cells lacking OX40 or 4-1BB signaling, survival is not compromised initially, but it is defective in the later divisions (Rogers et al., 2001; Cooper et al., 2002). The ligands are TNF-related transmembrane molecules, which emerge transiently, under strict control of antigen receptors and Toll-like receptors (Gravestein and Borst, 1998). CD70, the ligand of CD27, OX40 ligand (OX40L) and 4-IBB ligand (4-1 BBL) have all been found on activated T- and B lymphocytes and mature DC (Oshima et al., 1998; Tesselaar et al., 2003a; Al-Shamkani et al., 1996; Stuber et al., 1995; Futugawa et al., 2001), indicating that receptor/ligand interactions come into play during communication between T cells and antigen presenting cells as well as amongst effector T cells. Limited data are available on their expression in vivo. Deliberate constitutive expression of CD70, OX40L or 4-1 BBL by transgenesis upsets lymphocyte homeostasis, leading to immunodeficiency or auto-immunity, indicating that the transient availability of these ligands is crucial to prevent pathogenesis (Arens et al., 2001; Tesselaar et al., 2003b; Murata et al., 2002; Zhu et al., 2001). OX40 and OX40L-deficient mice have reduced primary CD4+ T cell responses to several viruses and common protein antigens (Kopf et al., 1999; Chen et al., 1999; Murata et al., 2000). Lower frequencies of antigen-specific effector CD4+ T cells are generated late in the primary response and fewer CD4+ memory T cells develop (Gramaglia et al., 2000). 82 OX40, 4-IBB and CD27 shape CD8+ Tcell memory In mice lacking 4-1 BBL, fewer antigen-specific CD8+ effector T cells and memory T cells develop (Tan et al., 1999; DeBenedette et al., 1999; Bertram et al, 2002). In CD27"A mice infected with influenza virus, accumulation of both CD4+ and CD8+ effector T cells is reduced (Hendriks et al., 2000). Phenotypes of receptor- and ligand deficient mice are subtle as compared to the phenotypes of mice in which the receptors are deliberately stimulated. Agonistic anti-OX40- or 4-IBB antibodies rescued T cells from activation- induced cell death and promoted memory formation (Maxwell et al, 2000; Takahashi et al., 1999). In CD70 transgenic mice, effector CD4+ and CD8+ T cells develop in the absence of deliberate antigenic challenge (Arens et al., 2001; Tesselaar et al., 2003b) and in non- immunized OX40L transgenic mice, CD4+ effector T cells accumulate. In addition, in OX40L transgenic mice CD4+ effector T cells showed decreased contraction after antigenic challenge (Murata et al., 2002). There are many data on the role of costimulatory receptors in primary responses, but much less is known about their importance for memory responses. We have found in the influenza virus model, that accumulation ofvirus-specific CD8+ effector T cells in the memory response is equally and critically dependent on both CD27 and CD28 (Hendriks et al., 2000; 2003). Intervention with OX40-Ig, as well as testing the performance of OX40"'" T cells in a model of virus-induced lung inflammation indicated that OX40 controls the accumulation of CD4+ effector cells in the memory response (Humphreys et al., 2003; Salek-Ardakani et al., 2003). In mice lacking 4-1BBL, accumulation of CD8+ effector T cells upon re-challenge with virus is reduced (Bertram et al., 2002). These data indicate that CD27 and 4-IBB are important for CD8+ memory responses and OX40 for CD4+ memory responses, but do not elucidate whether this is due to an effect on memory cell formation and/or responsiveness. We wondered whether CD27, OX40 and 4-IBB make complementary contributions to the same CD8+ T cell response. We therefore infected recombinant mice lacking relevant receptors or ligands with influenza virus and analysed the generation of CD8+ effector T cells, their conversion into memory T cells and memory cell responsiveness. We also monitored expression of receptors and ligands in lymphoid organs and lung throughout infection. Our results highlight the comlementarity between these receptor/ligand systems and revealed that OX40 and 4-IBB can endow CD8+ T cells with the capacity for secondary expansion during the primary response. Results Primary T cell responses to influenza virus in the absence of CD27, OX40L or 4-1BBL Intranasal challenge with influenza A virus NT/60/68 characteristically causes a dramatic influx effector T cells into the lung.