Crossroads Between Innate and Adaptive Immunity IV by Peter D. Katsikis Stephen P. Schoenberger & Bali Pulendran

Author:Peter D. Katsikis, Stephen P. Schoenberger & Bali Pulendran
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

8.2 CD28/B7 Costimulation in T Cell Function

CD28 is a 44 kDa glycoprotein expressed on the surface of T cells, plasma cells, and NK cells [18–20]. It binds to B7.1 (CD80) and B7.2 (CD86), which are expressed on dendritic cells, macrophages, B cells, and T cells [21–23]. The interaction between CD28 on T cells and B7.1/B7.2 molecules on antigen-presenting cells provides a crucial costimulatory signal required for the activation and optimal function of T cells [21, 22]. Since the CD28/B7 pathway has been extensively studied in T cells [24, 25], we will begin with an overview of how this pathway modulates T cell function. CD28 signaling in T cells leads to the activation of AKT, which stimulates numerous molecules including NF-κB, IL-2, and Bcl-XL; these molecules subsequently enhance activation, proliferation, and survival of T cells that have encountered antigen [26–28]. Moreover, the CD28/B7 costimulation is also involved in promoting metabolism in activated T cells so as to facilitate their effector functions [29]. Given the central role of CD28/B7 costimulation in T cell activation it is inevitable that T cells that recognize antigen without concurrent CD28 signaling become anergic.

The CD28/B7 costimulatory pathway was first identified as the critical second signal required for naive T cells activation [18] and its role in primary responses has been thoroughly investigated. Relatively fewer studies assessed the role of CD28/B7 on memory T cell responses, in part due to the widely held belief that memory T cells do not require costimulation. This belief was based on results from studies using in vitro reactivation memory T cells, which showed that unlike naive T cells, memory T cells can be activated by antigen without B7.1/B7.2 costimulation [30, 31]. A few in vivo studies corroborated the in vitro observation concluding that memory T cells do not require costimulation [32, 33]. In one of these studies by Suresh et al. they infected and rechallenged Cd28 −/− mice with LCMV and assessed their primary and secondary T cell responses. They showed that memory CD8 responses did not require CD28 costimulation [33]. Interestingly these mice exhibited a normal primary response suggesting that the LCMV infection system used here obviates the CD28 requirement for naive T cells; thus it is possible that this system bypasses the CD28 requirements for memory T cells as well. Conversely, a couple of studies demonstrated that memory T cells require dendritic cells for their optimal responses to infections with Listeria monocytogenes, vesicular stomatitis virus, and influenza virus [34, 35]. Given that the major role of DC in naive T cell activation is to provide costimulation and cytokines, the enhanced memory T cell responses in the presence of DCs suggested that perhaps memory T cells still need costimulation.

Indeed recent studies suggest that memory T cells need CD28 costimulation for optimal function [36]. This phenomenon was initially reported by Farber and colleagues; in this study they rechallenged adoptive hosts of influenza virus-specific memory CD4 T cells in the presence of CD28/B7 blocking agent- CTLA4-Ig or isotype control. They discovered that memory

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