CD4⁺T Cell Help Is Dispensable for Protective CD8⁺T Cell Memory against Mousepox Virus following Vaccinia Virus Immunization

Abstract

It has been shown in various infection models that CD4؉ T cell help (T H ) is necessary for the conditioning, maintenance, and/or recall responses of memory CD8 ؉ T cells (CD8 M) . Yet, in the case of vaccinia virus (VACV), which constitutes the vaccine used to eradicate smallpox and is a candidate vector for other infectious diseases, the issue is controversial because different groups have shown either T H dependence or independence of CD8 M conditioning, maintenance, and/or recall response. In agreement with some of these groups, we show that T H plays a role in, but is not essential for, the maintenance, proliferation, and effector differentiation of polyclonal memory CD8 ؉ T cells after infection with wild-type VACV strain Western Reserve. More important, we show that unhelped and helped anti-VACV memory CD8 ؉ T cells are similarly efficient at protecting susceptible mice from lethal mousepox, the mouse equivalent of human smallpox. Thus, T H is not essential for the conditioning and maintenance of memory CD8؉ T cells capable of mounting a recall response strong enough to protect from a lethal natural pathogen. Our results may partly explain why the VACV vaccine is so effective. IMPORTANCE We used vaccinia virus (VACV)-a gold standard vaccine-as the immunogen and ectromelia virus (ECTV) as the pathogen to demonstrate that the conditioning and maintenance of anti-VACV memory CD8 ؉ T cells and their ability to protect against an orthopoxvirus (OPV) infection in its natural host can develop in the absence of CD4؉ T cell help. Our results provide important insight to our basic knowledge of the immune system. Further, because VACV is used as a vaccine in humans, our results may help us understand how this vaccine induces protective immunity in this species. In addition, this work may partly explain why VACV is so effective as a vaccine. F ollowing primary viral infection or vaccination, naive antiviral CD8ϩ T cells (CD8 N ) contribute to virus control by expanding and becoming effectors (CD8 E ) that kill infected cells and produce antiviral cytokines such as gamma interferon (IFN-␥) (1). If the virus is eliminated, most CD8 E die but many survive to become resting memory CD8 ϩ T cells (CD8 M ) that remain at higher frequencies than the original CD8 N population (2). If a secondary infection occurs, the CD8 M rapidly expand and become secondary CD8 E . CD8 M can contribute to reduce the severity of a secondary viral infection by achieving high numbers of effectors more rapidly than CD8 N would. Moreover, the efficient generation of CD8 M may be important for the effectiveness of some vaccines.The genus Orthopoxvirus (OPV) comprises highly conserved DNA viruses that are antigenically highly cross-reactive. Vaccinia virus (VACV) is an OPV that can infect multiple species but is poorly pathogenic and highly immunogenic. Because of this, it was exploited as the vaccine that eliminated human smallpox, a highly lethal disease caused by the human-specific OPV variola virus (VARV). Thus, VACV remains as the gol...

Selective reconstitution of IFN‑γ gene function in Ncr1+ NK cells is sufficient to control systemic vaccinia virus infection

“…This model is supported by our data, showing that NK cell-derived IFN-γ is necessary to prevent the earlier published capacity of VACV to downregulate MHC-II expression on macrophages [54][55][56]. Previous studies already indicated that T cells were major producers of the second IFN-γ wave after VACV infection and that the presence of IFN-γ expressing CD8 + T cells was of key relevance to control the infection [15,18,57]. Nevertheless, we found that Ncr1-specific reconstitution of the IFN-γ gene function was sufficient to confer activation of the myeloid cell compartment upon VACV infection and to control the infection.…”

PARP-1/PARP-2 double deficiency in mouse T cells results in faulty immune responses and T lymphomas

“…Since primary virus infection was controlled by all genotypes ( Fig. 5D ), this suggests the possibility that the combination of a reduced CD8 + T-cell response with impaired CD4 + T-cells and antibody production during the acute response may explain virus control after primary infection even in the Cd4-cre;Parp2 f/f ;Parp1 −/− mice, as these three immune responses are each relevant to control VACV acute infection 39 40 .…”

CD4+T help promotes influenza virus-specific CD8+T cell memory by limiting metabolic dysfunction

“…As observed with primary CTL responses, memory CTL formation in certain circumstances can also be largely independent of CD4 + help, as observed after vesicular stomatitis virus (11) or ectromelia (mousepox) virus infection (12). Moreover, the extent of CD4 + T cell-dependence for the establishment of CTL memory can also vary for responses targeted to different peptides from the same immunogen (13).…”