Generation of Antiviral Major Histocompatibility Complex Class I-Restricted T Cells in the Absence of CD8 Coreceptors

Abstract

The CD8 coreceptor is important for positive selection of major histocompatibility complex I (MHC-I)-restricted thymocytes and in the generation of pathogen-specific T cells. However, the requirement for CD8 in these processes may not be essential. We previously showed that mice lacking ␤ 2 -microglobulin are highly susceptible to tumors induced by mouse polyoma virus (PyV), but CD8-deficient mice are resistant to these tumors. In this study, we show that CD8-deficient mice also control persistent PyV infection as efficiently as wild-type mice and generate a substantial virus-specific, MHC-I-restricted, T-cell response. Infection with vesicular stomatitis virus (VSV), which is acutely cleared, also recruited antigen-specific, MHC-I-restricted T cells in CD8-deficient mice. Yet, unlike in VSV infection, the antiviral MHC-I-restricted T-cell response to PyV has a prolonged expansion phase, indicating a requirement for persistent infection in driving T-cell inflation in CD8-deficient mice. Finally, we show that the PyV-specific, MHC-I-restricted T cells in CD8-deficient mice, while maintained long term at near-wild-type levels, are short lived in vivo and have extremely narrow T-cell receptor repertoires. These findings provide a possible explanation for the resistance of CD8-deficient mice to PyV-induced tumors and have implications for the maintenance of virus-specific MHC-I-restricted T cells during persistent infection.

Duality of the murine CD8 compartment

“…1 and 2 and Figs. S1 and S2) (2,12,14,17,32,36). The low-intensity calcium flux observed in CTL from KO mice likely is mediated, at least in part, by calcium channels other than CRAC, such as purigenic (P2X) and Ca v 1 channels that have been shown to support T-cell proliferation (36,37).…”

“…(iv) TCR sequences have been shown to convey CD8 dependence (2,14,(17)(18)(19)(20). (v) The TCR of a CD8-independent CTL engaged its ligands in a noncanonical docking orientation (23).…”

“…However, other studies claim that CD8 dependence is related to TCR sequences and that CD8-independent T cells can express lowaffinity TCR (2,(17)(18)(19)(20). This latter view is supported by the observations that CD8 independence or dependence can be conveyed by TCR gene transfer (18,20) and that the TCR repertoires of CD8-independent, virus-specific CTL from CD8β-or CD8α-KO mice are different from TCR repertoires of such CTL from normal mice (2,14,17). CD8 + (and CD4 + ) T cells are generated by a multistep process in the thymus.…”

Pathogen Stimulation History Impacts Donor-Specific CD8+ T Cell Susceptibility to Costimulation/Integrin Blockade Based Therapy

“…OT-I TCR transgenic cells were used to standardize the T cell precursor frequency, TCR fine specificity, and TCR affinity for OVA antigen between animals and treatment arms. 48 hours after adoptive transfer, mice were inoculated with one of three recombinant pathogens engineered to express the OVA epitope: 10 4 CFU of Listeria monocytogenes (LM)-OVA (33), 10 5 PFU of murine gammaherpesvirus 68 (gHV)-OVA (34), or 10 5 PFU of mouse polyoma virus (PyV)-OVA (35). LM and gHV were given intraperitoneally (i.p.)…”

Reply to “CD8 + T Cells Are Essential for Controlling Acute Friend Virus Infection in C57BL/6 Mice”

“…In fact, mice deficient in the CD8␣ chain (CD8 knockout) efficiently rejected MHC class I-disparate skin grafts even when they were depleted of CD4 ϩ T cells, and donor cell-specific cytotoxic activity was detected in the CD8 knockout recipient mice (7). Further, wild-type and CD8 knockout C57BL/6 (B6) mice were equally resistant to mouse polyomavirus infection, while ␤ 2 m-deficient mice were susceptible, and CD3 ϩ CD4 Ϫ T cells that bound to the MHC class I tetramer loaded with a D b -restricted, dominant polyomavirus epitope were detected in infected CD8 knockout mice (8,9). As MHC class I-restricted cytotoxic effector cells can be generated in the CD8 knockout mice Joedicke et al used, while such cells cannot lyse class I-deficient target cells, we would conclude that ␤ 2 m-deficient mice are better suited for evaluating the role of class I-restricted cytotoxic T cells in FV infection than CD8 knockout mice.…”