Protective CD8+ T cell memory without help.

CD8 T cells are a key component of the host adaptive immune responses that helps to eradicate invading virus and other cell-associated pathogens. The CD8 T cell responses to an acute infection consist of three well defined phases: naive pathogen-specific T cells (CD8N) become activated and expand resulting in large numbers of effector cells (CD8E); the contraction of these CD8E into memory cells (CD8M) once the infection is cleared; and the long-term maintenance of these CD8M. If a secondary infection occurs, the CD8M mount more vigorous and faster responses than CD8N, which help to rapidly and efficiently control the infection. The prolonged maintenance of this pool of antigen-specific CD8M can help protect from certain infections. Hence, one of the goals of vaccination is to generate CD8M. 
 
CD4 T cell help (TH) is essential for priming CD8 T cell responses to cell-associated, non-inflammatory antigens while being dispensable for responses generated to a variety of infectious pathogens. In several infectious models, TH is critical for the conditioning and/or maintenance of the CD8M pool and/or their secondary expansion and differentiation into secondary effectors. 
 
VACV is an orthopoxvirus (OPV) that was used as the vaccine that eliminated human smallpox, a highly lethal disease caused by the human-specific OPV variola virus (VARV). VACV is regarded as the golden standard of a highly effective vaccine. In addition to preventing smallpox, VACV is also effective as a vaccine against lethal mousepox, a disease caused by the mouse-specific OPV ectromelia virus (ECTV). We previously showed that in addition to antibodies, CD8M induced by VACV immunization can fully protect susceptible mice from lethal mousepox [1], suggesting that the establishment of a CD8M pool is one of the mechanisms whereby the smallpox vaccine protects from pathogenic OPVs. However, during the course of VACV infection or immunization, the role of TH for the generation, maintenance and recall responses of the anti-VACV CD8M remained controversial [2-6]. A possible explanation for these discrepancies may lie in the replicative capacity of the VACV strain used in different studies. Using a non attenuated VACV strain WR as the vaccine and ECTV as the pathogen, and by measuring polyclonal rather than transgenic CD8 T cells responses, we have recently shown that anti-VACV CD8M generated in the absence of TH that expand and differentiate into CD8E are as effective as helped CD8M in their ability to protect from lethal ECTV infection [7]. 
 
Consistent with some previous research, we found that wild type B6 mice and MHC-II-deficient mice (MHC-II0/0), which lack MHC-II restricted TH, mounted similar CD8 T cell responses during the acute phase of VACV infection (i.e. 7 days post immunization), indicating that optimal primary CD8 T cell responses to VACV are TH independent. After virus clearance, the frequency of CD8M specific for the VACV immunodominant determinant TSYKFESV (also an immunodominant determinant of ECTV) declined faster in MHC-II0/0 mice. However, most of the activation and memory markers were similar between the TSYKFESV-specific CD8M from wild type and MHC-II0/0 mice. Moreover, the unhelped CD8M expanded and generated secondary CD8M when maintained and boosted in the MHC-II deficient environment, and most of the activation and memory markers between the TSYKFESV-specific secondary CD8M from wild type and MHC-II0/0 mice were similar. 
 
The ultimate goal of CD8M is protecting from disease. To test the protective potential of the unhelped CD8M, we transferred secondary CD8M from wild type and MHC-II0/0 mice into B6.D2-(D6Mit149-D6Mit15) LusJ (B6.D2-D6) mice, a B6 congenic mouse strain that is susceptible to mousepox. Importantly, when adjusted to contain similar numbers of TSYKFESV-specific CD8M, the unhelped CD8M protected B6.D2.D6 mice as efficiently as helped CD8M. Transferring as few as 4.5×104 helped or unhelped TSYKFESV-specific CD8M significantly reduced the virus loads to similar lower levels and fully protected B6.D2-D6 mice from death. Thus, polyclonal anti-VACV CD8M generated in the absence or in the presence of TH are similarly potent at protecting mice from lethal ECTV infection on a per cell basis. 
 
Our results do not necessarily dispute that TH contribute to optimal maintenance of CD8M as the CD8M declined faster in MHC-II0/0 mice than that in WT mice. Yet, it is possible that this faster decline was due to the general poorer health of MHC-II0/0 mice, which are immunodeficent. Nevertheless, our work clearly shows that TH is not essential for the establishment of functional CD8M or to confer CD8M the capacity to protect from a lethal infection (Figure ​(Figure1).1). Because VACV is used as a vaccine in humans, our results may help us to understand how this vaccine induces protective immunity in people. 
 
 
 
Figure 1 
 
Conditioning and maintenance of anti-VACV CD8M and their protective capability to ECTV infection can develop without TH


Protective CD8 + T cell memory without help Min Fang and Luis J. Sigal
CD8 T cells are a key component of the host adaptive immune responses that helps to eradicate invading virus and other cell-associated pathogens. The CD8 T cell responses to an acute infection consist of three well defined phases: naïve pathogen-specific T cells (CD8 N ) become activated and expand resulting in large numbers of effector cells (CD8 E ); the contraction of these CD8 E into memory cells (CD8 M ) once the infection is cleared; and the long-term maintenance of these CD8 M . If a secondary infection occurs, the CD8 M mount more vigorous and faster responses than CD8 N , which help to rapidly and efficiently control the infection. The prolonged maintenance of this pool of antigen-specific CD8 M can help protect from certain infections. Hence, one of the goals of vaccination is to generate CD8 M .
CD4 T cell help (T H ) is essential for priming CD8 T cell responses to cell-associated, non-inflammatory antigens while being dispensable for responses generated to a variety of infectious pathogens. In several infectious models, T H is critical for the conditioning and/or maintenance of the CD8 M pool and/or their secondary expansion and differentiation into secondary effectors.
VACV is an orthopoxvirus (OPV) that was used as the vaccine that eliminated human smallpox, a highly lethal disease caused by the human-specific OPV variola virus (VARV). VACV is regarded as the golden standard of a highly effective vaccine. In addition to preventing smallpox, VACV is also effective as a vaccine against lethal mousepox, a disease caused by the mouse-specific OPV ectromelia virus (ECTV). We previously showed that in addition to antibodies, CD8 M induced by VACV immunization can fully protect susceptible mice from lethal mousepox [1], suggesting that the establishment of a CD8 M pool is one of the mechanisms whereby the smallpox vaccine protects from pathogenic OPVs. However, during the course of VACV infection or immunization, the role of T H for the generation, maintenance and recall responses of the anti-VACV CD8 M remained controversial [2][3][4][5][6]. A possible explanation for these discrepancies may lie in the replicative capacity of the VACV strain used in different studies. Using a non attenuated VACV strain WR as the vaccine and ECTV as the pathogen, and by measuring polyclonal rather than transgenic CD8 T cells responses, we have recently shown that anti-VACV CD8 M generated in the absence of T H that expand and differentiate into CD8 E are as effective as helped CD8 M in their ability to protect from lethal ECTV infection [7].
Consistent with some previous research, we found that wild type B6 mice and MHC-II-deficient mice (MHC-II 0/0 ), which lack MHC-II restricted T H, mounted similar CD8 T cell responses during the acute phase of VACV infection (i.e. 7 days post immunization), indicating that optimal primary CD8 T cell responses to VACV are T H independent. After virus clearance, the frequency of CD8 M

Figure 1: Conditioning and maintenance of anti-VACV CD8 M and their protective capability to ECTV infection can develop without T H .
The primary CD8 T cell responses to VACV were similar between wild type B6 mice and MHC-II 0/0 mice. Functional CD8 M were maintained in MHC-II 0/0 mice even though at lower frequency. When cell numbers are adjusted, the unhelped CD8 M from MHC-II 0/0 mice were similarly potent at protecting mice from lethal ECTV infection as the helped CD8 M from wild type mice. specific for the VACV immunodominant determinant TSYKFESV (also an immunodominant determinant of ECTV) declined faster in MHC-II 0/0 mice. However, most of the activation and memory markers were similar between the TSYKFESV-specific CD8 M from wild type and MHC-II 0/0 mice. Moreover, the unhelped CD8 M expanded and generated secondary CD8 M when maintained and boosted in the MHC-II deficient environment, and most of the activation and memory markers between the TSYKFESV-specific secondary CD8 M from wild type and MHC-II 0/0 mice were similar.
The ultimate goal of CD8 M is protecting from disease. To test the protective potential of the unhelped CD8 M , we transferred secondary CD8 M from wild type and MHC-II 0/0 mice into B6.D2-(D6Mit149-D6Mit15) LusJ (B6.D2-D6) mice, a B6 congenic mouse strain that is susceptible to mousepox. Importantly, when adjusted to contain similar numbers of TSYKFESV-specific CD8 M , the unhelped CD8 M protected B6.D2.D6 mice as efficiently as helped CD8 M . Transferring as few as 4.5×10 4 helped or unhelped TSYKFESV-specific CD8 M significantly reduced the virus loads to similar lower levels and fully protected B6.D2-D6 mice from death. Thus, polyclonal anti-VACV CD8 M generated in the absence or in the presence of T H are similarly potent at protecting mice from lethal ECTV infection on a per cell basis.
Our results do not necessarily dispute that T H contribute to optimal maintenance of CD8 M as the CD8 M declined faster in MHC-II 0/0 mice than that in WT mice. Yet, it is possible that this faster decline was due to the general poorer health of MHC-II 0/0 mice, which are immunodeficent. Nevertheless, our work clearly shows that T H is not essential for the establishment of functional CD8 M or to confer CD8 M the capacity to protect from a lethal infection (Figure 1). Because VACV is used as a vaccine in humans, our results may help us to understand how this vaccine induces protective immunity in people.