Seminars in Immunology 16 (2004) 185–196 Role of T cell costimulation in anti-viral immunity Edward M. Bertram a , Wojciech Dawicki b , Tania H. Watts b,∗ a Australian Phenomics Facility and Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, Australia 2601 b Department of Immunology, University of Toronto, Medical Sciences Blgd., Room 5263, 1 King’s College Circle, Toronto, Ont., Canada M5S 1A8 Abstract Members of both the CD28 and TNFR families can have costimulatory roles in T cell activation. Gene targeted mice as well as in vivo blocking experiments have established distinct roles for CD28/B7; ICOS/ICOSL; CD27/CD70; 4-1BB/4-1BBL and OX40/OX40L during viral infection. Many issues remain to be addressed, including the timing and location of the interactions, the possibility of partial redundancy between related family members and the molecular basis for the specific phenotypes observed in the different gene targeted mice. © 2004 Elsevier Ltd. All rights reserved. Keywords: CD28 family; TNFR family; Costimulation; Viruses; T cells 1. Introduction Costimulation refers to the concept that signals through the T cell receptor (TCR) alone are insufficient for full T cell activation, but rather a second signal must be pro- vided to achieve full T cell activation and survival. Although some viral CD8 T cell responses are relatively indepen- dent of CD28 [1], CD28 is widely considered to be the pri- mary costimulatory receptor for initial expansion and sur- vival of T cells [2,3]. In addition to CD28, a number of inducible receptor/ligand pairs can play a role in modulat- ing the quantity, quality or duration of immune responses. Although not all of them act independently of CD28 to in- duce T cell activation and survival, in this review we use the term costimulation rather loosely, to include members of the CD28 [3] and TNFR families [4,5] that have a positive role on the responses of na¨ ıve, effector, or memory T cells (Fig. 1). Several new members of the CD28/B7 receptor/ligand family have recently been identified [3,6]. Among these, in- ducible costimulator (ICOS) plays an important role in ger- minal center formation and in CD4 T cell help for antibody production [3,6–12]. Other members of the CD28/B7 family inhibit T cell responses [3], and the expression of inhibitory Abbreviations: DLN, draining lymph node; TNFR, tumor necrosis factor receptor; TRAF, TNF receptor associated factor; TIM, TRAF in- teracting motif; TK, thymidine kinase ∗ Corresponding author. Tel.: +1-416-978-4551; fax: +1-416-978-1938. E-mail address: tania.watts@utoronto.ca (T.H. Watts). ligands at inflammatory sites may limit the effects of the costimulatory members of the family [13]. In addition to the CD28 family, several members of the TNFR family play a role in T cell activation. TNFR members fall into three major groups; (i) those that contain death domains that link surface receptors to programmed cell death pathways, (ii) decoy receptors that lack signal- ing domains and (iii) TNFRs that lack death domains but contain TRAF interacting motifs (or TIMs) [14], that link cell surface receptors to upregulation of NF-B and stress kinase signaling [15]. Although the membrane proximal events in TNFR family and CD28 family signaling are quite distinct, TCR plus CD28 signaling and signaling by TRAF-binding TNFR family members have in common the downstream activation of survival (NF-B) and stress ki- nase signaling [15,16]. Among the TIM-containing TNFR family members, OX40 (CD234)/OX40L CD27/CD70, 4-1BB (CD137)/4-1BBL have been well established as having stimulatory activity for T cells activation (reviewed in [4,5]). Other TRAF-binding members of the TNFR/TNF ligand family including CD30/CD30L and HVEM/LIGHT also appear to have stimulatory effects for T cells [17–20]. On APC, TNFR family members CD40 and RANK are im- portant in survival signaling and activation of APC, which in turn can effect T cell responses [21–23]. Although much has been learned about costimulation through studying responses to model antigens, to fully ap- preciate the role of costimulatory molecules in the immune response it is important to test their function in vivo during an actual infection. Replication of pathogens increases the 1044-5323/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.smim.2004.02.006