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The Journal of Immunology, 2001, 167: 1333-1337.
Copyright © 2001 by The American Association of Immunologists

The Role of p53 in Regulating Antiviral T Cell Responses1

Jason M. Grayson, J. Gibson Lanier, John D. Altman and Rafi Ahmed2

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
It is now well established that viral infections can induce large expansions of Ag-specific CD8+ T cells. These cells divide very rapidly with an estimated doubling time of ~6 h. When virus is cleared, the vast majority of these effector CD8 T cells undergo apoptosis. The remaining memory cells persist at constant levels and provide the basis for the accelerated recall response upon rechallenge. The molecular mechanisms that control the rapid proliferation and death of Ag-specific T cells are poorly understood. Because of its important role in controlling cell proliferation and death, we examined antiviral immune responses in p53-/- mice using lymphocytic choriomeningitis virus. We found that effector CD8 and CD4 responses were comparable but that memory levels were slightly higher in -/- mice compared with +/+ mice. The lack of a major difference in virus-specific T cell responses between +/+ and -/- mice suggests that p53 only plays a minor role in regulating the proliferation, apoptosis, and maintenance of Ag-specific T cells. Thus, it appears that the primary function of p53 is in controlling "illegitimate" proliferation and tumor development and not in regulating Ag-specific T cell responses.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
All organisms must carefully balance cell growth and death. Unchecked growth is a key step in oncogenesis (1), whereas excessive death is a feature in some diseases including Alzheimer’s, Parkinson’s disease, and amyotrophic lateral sclerosis (2). To prevent such deleterious outcomes, cells tightly couple proliferative and death pathways. Several cell cycle regulators such as E2F1, Myc, and p53 have been shown to either cause proliferation or death depending upon the context (3). p53 was originally identified as a protein complexed with large T Ag of SV40 virus (4) but was later shown to be a tumor suppressor and cell cycle regulator. Animals that contain a targeted mutation in the p53 gene develop malignancies, primarily lymphoma, at 6 mo of age (5). The clinical importance of p53 is demonstrated by the fact that many human malignancies have a mutation in the p53 gene itself or in some part of the pathway in which it functions (6). The p53 protein is a tetrameric transcription factor that serves as the "guardian of the genome" (7). Signals such as irradiation, chemotoxic agents, hypoxia, and exposure to heavy metals cause DNA binding and activation of transcriptional targets (8). Depending on the amount and duration of the stimulus, there are two possible outcomes: cell cycle arrest in G1/G2 or apoptosis (9).

During acute viral infection, there is often a very large proliferation of Ag-specific CD8+ and CD4+ T cells. After clearance of the virus, 90–95% of the Ag-specific effector cells undergo apoptosis. The surviving memory cells can persist for the life of the animal and rapidly assume effector functions upon re-encounter with Ag (10). Memory cells undergo a slow homeostatic proliferation that is class I independent (11). The genes that control this massive expansion and contraction remain unclear. Previous studies examining the immune response to lymphocytic choriomeningitis virus (LCMV)3 in mice that contain mutations in the Fas pathway (12) or in TNFR I (13, 14) have shown that the absence of either molecule has only a marginal effect on the final size of the memory pool.

Because of its critical role in cell cycle control and apoptosis, we decided to examine the immune response to LCMV in mice that contained a targeted mutation in the p53 gene. We found that, at the peak of the effector response, wild-type (wt) and mutant mice made comparable responses. By the time the memory phase was established, mutant mice contained slightly more memory cells than wt mice.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Virus infection and mice

Female 6- to 8-wk-old C57BL/6 and p53-/- mice were purchased from Taconic Farms (Germantown, NY). These mice were infected i.p. with 2 x 105 PFU LCMV-Armstrong and used at the indicated time points. For secondary challenge experiments, immune mice were injected i.v. with 2 x 106 PFU LCMV-clone 13 and used at the indicated time points. Virus stocks were grown and quantitated as described previously (15).

Preparation of MHC class I tetramers

The construction of Db gp33–41, Db NP396–404, and Db gp276–286 MHC class I tetramers has been described previously (10).

Flow cytometry and FACS analysis

Preparation of cells and staining has been described previously (10).

CTL assay

Cytotoxicity was assessed in a 5-h 51Cr-release assay as described previously (10).

Intracellular cytokine staining

Intracellular cytokine staining was performed as described previously (10).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
To determine the role of p53 in Ag-driven T cell expansion and death, we infected wt and p53-/- mice with LCMV. Animals were sacrificed 8 days after infection at the peak of the antiviral response. We performed cytotoxicity assays to compare the CTL responses in both wt and null mice. As shown in Fig. 1Go, the CTL activity was similar in wt and p53-/- mice. Both strains mounted a vigorous CTL response with ~80% specific release at an E:T ratio of 50:1, and both had cleared the virus by day 8 after infection (<50 PFU/ml in the serum; data not shown). Because both strains had vigorous CTL responses, we decided to examine overall T cell responses. LCMV induces a very large expansion of Ag-specific CD8+ and CD4+ T cells. The wt mice contained comparable numbers of CD8CD44high cells as p53-/- mice (9.89 ± 1.77 x 107 vs 7.55 ± 2.39 x 107; Fig. 2GoA). Enumeration of CD4CD44high cells showed that wt mice also contained similar numbers of this cell type as well (7.49 ± 2.89 x 106 vs 6.97 ± 1.68 x 106; Fig. 2GoB). When Ag-specific CD8+ T cells were identified by intracellular cytokine staining (Fig. 2GoC), there were similar numbers of cells for the three immunodominant epitopes Db gp33–41/Kb gp34–41 (1.84 x 107 ± 4.61 x 106 (wt) vs 1.57 x 107 ± 3.55 x 106 (-/-), Db NP396–404 (1.76 x 107 ± 3.43 x 106 vs 1.43 x 107 ± 5.04 x 106), and Db gp276–286 (6.21 x 106 ± 7.36 x 105 vs 5.74 x 106 ± 1.65 x 106). In addition to assessing the CD8 response, we also examined the ability of p53-null mutants to mount an Ag-specific CD4 response. In Fig. 2GoD, we show that these animals generated comparable numbers of IFN-{gamma}-producing Ag-specific cells compared with wt mice for two MHC class II IAK-restricted epitopes gp61–80 (1.89 x 106 ± 9.12 x 105 (wt) vs 1.82 x 106 ± 5.80 x 105 (-/-) and NP309–325 (6.24 ± 3.02 x 105 vs 4.87 ± 1.52 x 105).



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  		FIGURE 1. The wt and p53-null mice mount vigorous CTL responses. Splenocytes from wt and p53-null mice 8 days after infection with LCMV-Armstrong were harvested and incubated directly ex vivo at the indicated E:T ratio with 51Cr-labeled H-2b targets that were either untreated (closed symbols) or infected (open symbols) with clone 13 LCMV in a 5-h 51Cr-release assay. Each sample was assayed in triplicate.

 


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  		FIGURE 2. The wt and p53 mice generate comparable T cell responses. The wt and p53-null mice were infected with LCMV-Armstrong, and splenocytes were harvested 8 days after infection. CD8+ (A) and CD4+ (B) CD44high cells were enumerated by surface staining with CD8 or CD4 and CD44 Abs and FACS analysis. Ag-specific cells were enumerated by culturing splenocytes in vitro with peptides for CD8 (C) or CD4 (D) epitopes for 5 h followed by surface staining for CD8 or CD4 and intracellular staining for IFN-{gamma}. Data presented are the average derived from two experiments with four to six mice, and the bars indicate SD.

 
After viral clearance, Ag-specific CD8+ T cell responses contract to allow the immune system to return to homeostasis. To determine whether p53 influences the in vivo death of Ag-specific cells, we performed longitudinal analysis of PBL as the response contracts. Fig. 3Go shows tetramer analysis of the Db-restricted epitope gp33–41. On day 8 after infection, CD8+gp33–41+ cells constitute 9.0 and 7.7% of wt and mutant CD8+ PBL. By day 15, the numbers of cells had decreased to 4.9% in wt and 5.1% in the mutant and stabilized at 3.5 and 3.8% on day 38 for both strains. Similar trends are observed for NP396–404-positive and gp276-positive CD8+ PBL (data not shown).



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  		FIGURE 3. Contraction of antiviral responses proceeds in vivo in the absence of p53. The wt and p53-null mice were infected with LCMV, and PBL were analyzed 8, 15, and 38 days after infection. Cells were surface stained with CD8 Abs and Db gp33–41 tetramer. The number indicates the percentage of CD8 cells that stained positive for each tetramer. The data shown are from a representative mouse from a group of three to five mice.

 
After contraction of the CD8 response, the surviving Ag-specific cells enter the memory phase. We first examined whether total numbers of activated/memory phenotype (CD44highCD8+CD4+ T cells) was different between the two states. Mutant animals contained 7.27 ± 1.53 x 106 CD8+CD44high cells compared with wt, which contained 4.04 x 106 ± 4.64 x 105 cells (Fig. 4GoA). The difference in activated/memory phenotype was also observed in the CD4 compartment, where mutant animals contained 7.3 ± 1.63 x 106 CD4CD44high cells compared with the wt animals, which contained 3.54 x 106 ± 4.06 x 105 cells (Fig. 4GoB). To assess whether this difference was due to an increase in Ag-specific cells, we performed intracellular cytokine staining to enumerate Ag-specific cells. Comparison of Ag-specific CD8+ T cells by intracellular cytokine staining revealed slightly higher numbers of cells for all three immunodominant epitopes (gp33–41/gp34–41, 4.07 x 105 ± 8.94 x 104 (wt) vs 6.17 ± 3.91 x 105 (-/-); NP396–404, 3.03 x 105 ± 6.91 x 104 vs 5.86 ± 1.60 x 105; and gp276–286, 1.93 x 105 ± 4.77 x 104 vs 2.25 x 105 ± 1.42 x 105; Fig. 4GoC) in mutant mice. Similar results were observed when cells were enumerated with MHC class I tetramers. When the CD4 epitopes were examined (Fig. 4GoD), there were slightly greater numbers of gp61–80-specific (1.45 x 105 ± 8.41 x 104 (-/-)- vs 8.75 ± 3.49 x 104 (wt)) and NP309–325-specific (7.34 x 104 ± 7.57 x 103 vs 3.96 x 104 ± 5 x 103) CD4+ memory T cells.



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  		FIGURE 4. The p53-null mice generate slightly more memory T cells than wt mice. The wt and p53-null mice were infected with LCMV-Armstrong, and splenocytes were harvested 90 days after infection. A, CD8+ and CD4+CD44high cells were enumerated by surface staining with CD8 or CD4 and CD44 Abs and FACS analysis. Ag-specific cells were enumerated by culturing splenocytes in vitro with peptides for CD8 (C) or CD4 (D) epitopes for 5 h followed by surface staining for CD8 or CD4 and intracellular staining for IFN-{gamma}. Data presented are the average derived from two mutant and four wt mice, and the bars indicate SD.

 
Given p53’s role in proliferation and oncogenesis, we wanted to test whether re-exposure of memory cells to infection would result in expansion and contraction of these cells. To address this question, we performed longitudinal analysis on PBL from animals that were rechallenged with LCMV-clone 13. Infection of immune animals with this strain results in activation and proliferation of Ag-specific CD8+ T cells. Fig. 5Go demonstrates the percentage of CD8+NP396+ T cells increased from 7.1 to 54.9% in the wt mice and from 9.9 to 45.8% in the mutant mice by day 4 of secondary infection. Similar increases were observed for CD8+gp276+ T cells. By day 34 after infection, the numbers of NP396+ and gp276+ cells had decreased by 2-fold in both the wt and mutant mice. The limited recruitment of gp33–41-specific CD8+ T cells has been documented before (16).



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  		FIGURE 5. Contraction of secondary antiviral responses proceeds in vivo in the absence of p53. The wt and p53-null LCMV-Armstrong-immune (day 50) mice were infected with LCMV-clone 13, and PBL were analyzed 4 and 34 days after infection. Cells were surface stained with CD8 Abs and Db gp33–41 (A), Db NP396–404 (B), or Db gp276–286 (C) tetramer. The number indicates the percentage of CD8 cells that stained positive for each tetramer. The data shown are from a representative mouse from a group of three to five mice.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we examined the role of p53 in the expansion and death of Ag-specific CD8+ and CD4+ T cells during an acute viral infection. We found that the expansion of Ag-specific CD8+ and CD4+ T cells was marginally affected by the absence of p53. In addition to expansion, we observed that death of effector cells in vivo was also reduced slightly in mutant mice. Once cells entered the memory phase, homeostasis appeared to be maintained, and both strains were able to mount and a vigorous secondary response to LCMV.

What are the implications for p53’s role in T cell responses? Previous studies have demonstrated that p53 is a critical cell cycle and apoptosis regulator. Overexpression of p53 can halt cell cycle in either G1 or G2 (17). It is important to examine p53’s role in the context of T cell proliferation. When a naive T cell enters the periphery, it is in a resting state, undergoing little proliferation (18). However, if a naive cell encounters Ag in the appropriate context, it will begin a period of rapid proliferation that will be accompanied by elaboration of effector functions (10, 19). Finally, memory cells undergo a slow homeostatic proliferation that is slower than Ag-driven proliferation and is MHC class I independent (11). In our study, we have clarified the role of p53 in several of these types of T cell proliferation. First, we demonstrate that the overall expansion of effector cells appears to be normal in both strains of mice. This result is surprising given that loss of p53 causes cells to bypass cycling checkpoints and divide. The homeostatic maintenance of memory cells appears to be normal, because relatively constant numbers of memory cells were maintained for the periods examined in our study (3–6 mo). Other investigators have observed that uninfected p53-null animals contain greater numbers of CD8+ and CD4+CD44high cells (20). We also observed that LCMV-immune p53-null animals contain greater numbers of these cells.

In addition to its role in controlling cell cycle progression, p53 has the ability to cause apoptosis in response to some stimuli such as DNA damage following irradiation (21) or exposure to genotoxic chemotherapeutics. The exact mechanisms by which p53 performs this function are unclear, but it is thought to involve transcription of genes including Bax (22), Gadd 45 (23), and APAF-1 (24). In the context of T cell development, there are multiple times when T cells have an opportunity to undergo programmed cell death. First, developing T cells must survive death by neglect and negative selection in the thymus. Naive cells entering the periphery do not divide and appear to persist for several months. Once cells become activated, they proliferate and differentiate into effector cells that undergo a period of extensive cell death after Ag is cleared. Finally, in the memory pool, numbers remain constant, although a minor fraction of the cells are dividing at any given time. The constancy of numbers in the presence of proliferation suggests some death occurs to maintain equal numbers. Previous studies have shown thymocytes and resting naive cells from p53-null animals are more resistant to irradiation (21) and other genotoxic stimuli (25). We show that in vivo death of activated Ag-specific cells is slightly reduced in mutant mice. This extends a previous report demonstrating that T cells from p53-/- mice activated in vitro will undergo apoptosis after ligation of their TCR (22). Although we observe a minor effect on T cell expansion and death, our results are very similar to a study of sepsis that found p53 did not play a major role in the death of lymphocytes (26). The death of Ag-specific effector cells was slightly reduced after both primary and secondary infection, but we did not examine death during chronic infection. In chronic LCMV infection, some effector cells are physically deleted early in the infection (27). A study by Zhou et al. (28) determined that it was easier to generate CTL lines from p53-null mice than wt mice. Given that CTL lines are generated by continual growth in peptide, it would be of interest to determine whether p53-null effector cells would survive longer after chronic exposure to Ag. Our study focused on T cell proliferation and death, but studies of B cell proliferation after mitogen activation or infection with EBV also showed that p53 induction did not result in cell cycle arrest or apoptosis (29). Recent studies have implicated E2F1-based activation of p73, a p53 family member, as a critical event in TCR-mediated death (30). This may explain why death of activated cells induced by TCR ligation or viral infection is not significantly affected in the absence of p53. Interestingly, it raises yet another question: What is the signal that p73 recognizes in an activated T cell that p53 does not?

In conclusion, we have demonstrated that at the peak of the effector response on day 8, the wt mice contain similar numbers of Ag-specific T cells compared with mutant mice. By the time the memory phase was established, the mutant mice contained slightly higher numbers of memory cells compared with wt mice. This effect is marginal and suggests that p53 plays a relatively minor role in the expansion and contraction of T cell responses. Additionally, we have shown that immune memory is maintained in these animals, and they are able to mount vigorous anamnestic responses.


   Footnotes
 
1 This research was supported by National Institutes of Health Grants AI30048 (to R.A.) and NS 21496 (to R.A.). J.M.G. was supported by National Research Service Award 1F32AI0249-01A1. Back

2 Address correspondence and reprint requests to Dr. Rafi Ahmed, Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, G211 Rollins Research Building, 1510 Clifton Road, Atlanta, GA 30322. E-mail address: ra{at}microbio.emory.edu Back

3 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; NP, nucleoprotein; wt, wild type. Back

Received for publication March 21, 2001. Accepted for publication May 30, 2001.


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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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