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The Journal of Immunology, 2004, 172: 6533-6537.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Effector Memory CD8+ T Cells Play a Prominent Role in Recall Responses to Secondary Viral Infection in the Lung1

Alan D. Roberts and David L. Woodland2

Trudeau Institute, Saranac Lake, NY 12983


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The relative contributions of CD62Lhigh (central) memory and CD62Llow (effector) memory T cell populations to recall responses are poorly understood, especially in the respiratory tract. In this study, we took advantage of a dual-adoptive transfer system in the mouse to simultaneously follow the recall response of effector and central memory subpopulations to intranasal parainfluenza virus infection. Using MHC class I and class II multimers, we tracked the responses of Ag-specific CD8+ and CD4+ memory T cells in the same animals. The data show that effector memory T cells mounted recall responses that were equal to, or greater than, those mounted by central memory T cells. Moreover, effector memory T cells were more efficient at subsequently establishing a second generation of memory T cells. These data contrast with other studies indicating that central memory CD8+ T cells are the prominent contributors to systemic virus infections.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Tlymphocytes play a central role in controlling respiratory virus infections (1). Following clearance of the infection, populations of Ag-specific memory T cells are established that have the capacity to mediate accelerated and more vigorous responses to secondary viral challenge (1). Memory T cells persist in both lymphoid and peripheral tissues and can be resolved into two major subsets based on their expression of lymph node homing receptors (CD62L and CCR7), referred to as central and effector memory T cells (1, 2, 3, 4, 5, 6, 7, 8, 9, 10). Whereas central memory T cells (CD62LhighCCR7+) are predominantly found in lymphoid tissues, effector memory T cells (CD62LlowCCR7–) are found in both lymphoid and peripheral tissues (10, 11). The relative contribution of these different subpopulations to recall responses is poorly understood (12, 13). One possibility is that effector memory cells present an immediate, but not sustained, defense at pathogen sites of entry, whereas central memory T cells sustain the response by proliferating in the secondary lymphoid organs and producing a supply of new effectors (14, 15, 16). Consistent with this idea, effector memory T cells in the lung airways have been shown to mediate early control of respiratory virus challenge (4, 17). Furthermore, Wherry et al. (11) analyzed the recall response to systemic lymphocytic choriomeningitis virus (LCMV)3 (1) infection and showed that CD62Lhigh (central) memory CD8+ T cells respond more vigorously to secondary challenge than CD62Llow (effector) memory T cells in terms of their expansion and capacity to clear virus. However, there is little information on how these memory T cell subsets (either CD4+ or CD8+) contribute to the recall response to mucosal, rather than systemic, infections. To address this issue, we have investigated the proliferative response of CD4+ and CD8+ memory T cells to Sendai virus infection in the lung. The data show that CD62Llow (effector) memory T cells are able to generate a recall response that is at least as strong as that mediated by CD62Lhigh (central) memory T cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Viruses, mice, and infection

Male C57BL/6, B6.Pl-Thy1a/Cy (Thy1.1), and B6.SJL-Ptprca Pep3/BoyJ (CD45.1) mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed under specific pathogen-free conditions. Anesthetized mice were intranasally infected with 250 50% egg infectious doses of Sendai virus (Enders strain) (2).

Adoptive transfers

Spleens from B6.Pl-Thy1a/Cy (Thy1.1) and B6.SJL-PtprcaPep3/BoyJ (CD45.1) donor mice that had recovered from a prior Sendai virus infection were depleted of erythrocytes, panned on goat anti-mouse IgG H+L (Jackson ImmunoResearch Laboratories, West Grove, PA)-coated Primaria flasks (Falcon; BD Discovery Labware, Bedford MA) to remove B cells and macrophages, and then further enriched for either CD8+ or CD3+ T cells using negative selection columns (R&D Systems, Minneapolis, MN). Cells were then stained with CD62L-FITC, CD44-PE, CD8-PE/CY5 (CD8+ enriched), or CD62L-FITC and CD44-PE (CD3+ enriched) for sorting on a FACSVantage (BD Immunocytometry Systems, San Jose, CA) cell sorter with DIVA enhancement software. Sort gates were set for CD44+CD8+ (or just CD44+) and CD62L (as illustrated in Fig. 1). The CD62Llow- and CD62Lhigh-sorted cell populations were then mixed, labeled with 0.5 µM CFSE for 10 min at room temperature, washed, and adoptively transferred i.v. into naive C57BL/6 recipient mice (typically three recipients per experiment). One day later, mice were challenged intranasally with 250 50% egg infectious doses of Sendai virus. At various days postinfection (see Table I), bronchoalveloar lavage (BAL), mediastinal lymph nodes (MLN), lungs, and spleens were harvested, and lymphocyte populations were stained as described previously (1, 2, 4, 8). The data were acquired using a FACSCalibur flow cytometer (BD Immunocytometry Systems) and analyzed with FlowJo software (Tree Star, Ashland, OR).



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  		FIGURE 1. Isolation of memory cell subsets. CD8-enriched spleen cells were flow-cytometrically separated into memory T cell subsets by gating on CD44highCD8+ cells (A) and then sorting on the basis of CD62L expression (B). Sorted populations were >95% pure (C and D). Samples of the sorted populations were stained with NP324–332/Kb multimer to determine the percentage of NP324–332/Kb-specific T cells in each sorted population (E and F). In some experiments (experiments 5 and 6), the cells were isolated and purified using the same protocol, with the exception that the CD8 Ab was excluded. The numbers in B–F indicate the percentages of cells in the marked regions.

 

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  		Table I. Preferential contribution of CD62Llow memory cells in the recall response to Sendai virus infection

 

   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Previous studies have shown that populations of CD8+ memory T cells specific for the immunodominant nucleoprotein (NP)324–332/Kb epitope are established in various organs following the recovery of C57BL/6 mice from an intranasal Sendai virus infection (2). Typically, 200,000 NP324–332/Kb-specific cells persist in the spleen, and the majority of these express an effector memory phenotype based on CD62L expression (2). To investigate the contribution of these memory cell subsets to pulmonary recall responses, we compared their capacity to respond to a Sendai virus challenge in an adoptive transfer system. CD8+CD44+CD62Llow or CD8+CD44+CD62Lhigh memory cells were isolated from Thy1.1 mice by flow-cytometric cell sorting (the purity of the cells was always >=95%, as illustrated by a typical sort in Fig. 1). Sorted cells were then CFSE labeled and i.v. transferred to recipient C57BL/6 (Thy1.2) mice before intranasal Sendai virus infection 1 day later. The numbers of donor and host NP324–332/Kb-specific T cells were subsequently determined in different organs at various times postinfection. In preliminary studies (data not shown), we observed substantial expansion of NP324–332/Kb-specific T cells in all tissues tested, peaking between days 9 and 11 postinfection. Typically, the CD62Llow memory T cells generated responses equivalent to, or better than, CD62Lhigh memory T cells in terms of the numbers of donor NP324–332/Kb-specific T cells recovered (data not shown). This expansion was Ag dependent, because Sendai virus-specific memory cells did not expand in uninfected or influenza virus-infected mice.

Although these preliminary data demonstrated a strong expansion of CD62Llow memory T cells, variation between individual recipients made it difficult to directly compare the expansion of the CD62Llow and CD62Lhigh subsets. To get around this problem, we developed a dual-transfer protocol using CD44+CD62Llow and CD44+CD62Lhigh memory T cells isolated from CD45.1 (Ly-5.1) and CD90.1 (Thy1.1) donors (as illustrated in the diagram in Fig. 2). Sorted cells were labeled with CFSE and then mixed together such that the number of NP324–332/Kb-CD62Llow and NP324–332/Kb-CD62Lhighmemory T cells was at the original splenic ratio, or at a 1:1 ratio. The cells were then transferred i.v. into C57BL/6 (CD45.2/CD90.2) recipient mice, which were intranasally infected with Sendai virus 1 day later. At various times postinfection, the numbers of NP324–332/Kb-specific donor T cells in various tissues were determined on the basis of CD45.1 and CD90.1 expression. Data from six individual experiments and a representative example of the flow-cytometric analysis are presented in Table I and Fig. 2.



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  		FIGURE 2. Expansion of CD62Llow (effector) memory CD8+ T cells. Mixtures of CFSE-labeled CD44+CD62Lhigh and CD44+CD62Llow memory T cells were transferred into two groups of C57BL/6 recipient mice. The first group of mice (A) received a mixture of CD44+CD62Llow T cells from CD45.1 donors and CD44+CD62Lhigh T cells from CD90.1 donors. The second group of mice (B) received CD44+CD62Llow T cells from CD90.1 donors and CD44+CD62Lhigh T cells from CD45.1 donors. Recipient C57BL/6 mice (CD45.2/CD90.2) were then intranasally infected with Sendai virus 1 day later. Eleven days postinfection, cells were recovered from the lung airways and stained for the expression of CD8 and each of the congenic markers (CD45.1 and CD90.1, left column). The boxes indicate gates that identify host or donor CD8 cells, which are then analyzed for multimer (NP324–332/Kb) and CFSE expression (middle and right-hand columns). The data in this figure are derived from experiments 5 and 6 in Table I.

 
In general, there was a very strong expansion of Ag-specific donor cells to Sendai virus challenge, ranging from 7 to 80 times the input cell number at day 11 postchallenge. Furthermore, all of the Ag-specific donor T cells were CFSE negative, indicating that they had undergone at least seven divisions since transfer (Fig. 2). The advantage of the dual-transfer approach was that we were able to directly compare the expansion of the two subsets of transferred cells within individual mice. This revealed that there was a very strong expansion of the CD62Llow subset during the acute response to Sendai virus challenge that was greater than that of the CD62Lhigh subset in all experiments (i.e., the ratio of CD62Llow to CD62Lhigh donor cells recovered was increased relative to the input ratio; p = 0.006 in a binomial test). This was true regardless of whether the two subsets were initially transferred at a ~1:1 (CD62Llow to CD62Lhigh) ratio, or their original ratio in the donor mice (usually between 4:1 and 10:1, CD62Llow to CD62Lhigh). The strong expansion of the CD62Llow subset was observed in all tissues tested (spleen, MLN, lung parenchyma, and lung airways) and at both days 7 and 11 postinfection (Table I and data not shown). Similar data were also obtained when we analyzed the cells for cytokine production following stimulation with the NP324–332 peptide in an intracellular IFN-{gamma} assay (data not shown).

The strong expansion of CD62Llow memory T cells could not be attributed to an unanticipated effect of one of the genetic markers, because the same results were obtained regardless which marker was used to distinguish each T cell subset (Fig. 2, compare A and B). Similarly, the strong expansion of CD62Llow cells was not limited to recently established donor memory cells, because the data in experiments 5 and 6 were generated with donor memory cells that had been isolated 5 mo postinfection (Table I). However, it was possible that the isolation procedure affected the subsequent survival or response of the cells after transfer. Thus, we compared the survival of transferred CD62Llow and CD62Lhigh memory donor cells in the absence of infection, or after an irrelevant influenza virus infection (infected on day 1 posttransfer). Although the absolute numbers of memory cells recovered after 3 wk were relatively low, both CD62Llow and CD62Lhigh donors were readily identified in the spleen and lymph nodes, and each subset had retained its original phenotype (data not shown). This is consistent with earlier studies indicating that ligation with the CD62L Ab does not affect the precursor frequency or recall of memory T cells (18). Together, these data suggest that the isolation procedure does not favor the survival of either effector or central memory T cells in this transfer model.

We next considered the possibility that CD4+ T cells affected the recall response of memory CD8+ T cell subsets. This was an important issue, because many of our transfer studies were with memory T cells that had been purified on the basis of CD8+ expression. However, some of the transfer studies used cells isolated on the basis of CD44 and CD62L, but not CD8 (Table I, experiments 5 and 6). With this protocol, not only both effector and central CD8+ memory T cell populations, but also a full complement of memory CD4+ T cells are present. Again, CD62Llow memory T cells responded strongly to acute Sendai virus challenge and mediated responses that were at least as good, if not better than, CD62Lhigh memory T cells. To confirm that CD4+ T cells were indeed transferred and responding in these experiments, we used a multimer reagent that specifically detects T cells specific for the immunodominant hemagglutinin-neuraminidase (HN)419–433/Ab epitope (8). As shown in Fig. 3, there was a strong expansion of HN419–433/Ab-specific donor T cells during the acute response to Sendai virus challenge. It should be noted that the data in Fig. 3 are from the same experiment shown in Fig. 2 and represent responses that were occurring concomitantly with the CD8 responses in the same animals. Thus, the preferential expansion of CD62Llow memory CD8+ T cells cannot be attributed to an absence of memory CD4+ T cells. Interestingly, the recovery of HN419–433/Ab-specific donor T cells was also biased to cells derived from the CD62Llow subset during the acute infection (day 11) (Table I). These data indicate that effector memory CD4+ T cells also respond vigorously to secondary virus challenge and that they are at least as efficient as, if not superior, to central memory cells in terms of their ability to mediate recall responses.



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  		FIGURE 3. Expansion of CD62Llow (effector) memory CD4+ T cells. Mixtures of CFSE-labeled CD44+CD62Lhigh and CD44+CD62Llow memory T cells were transferred into two groups of C57BL/6 recipient mice (using the same basic protocol illustrated in Fig. 2). Recipient mice were then intranasally infected with Sendai virus 1 day later. Eleven days postinfection, cells were recovered from the lung airways and stained for the expression of CD4 and each of the congenic markers (CD45.1 and CD90.1, left column). The boxes indicate gates that identify host or donor CD4 cells, which are then analyzed for multimer (HN419–433/Ab) and CFSE expression (middle and right-hand columns). The data in this figure are derived from experiments 5 and 6 in Table I.

 
Given the strong proliferative response of Ag-specific CD62Llow memory T cells to Sendai virus challenge, we next investigated whether these cells contributed to the re-establishment of memory T cells. In three different experiments, there was a strong bias in the spleen toward the re-establishment of memory T cells from the CD62Llow donor population (Table I, experiments 3, 4, and 6). A similar bias was observed in the lung airways in experiments 3 and 4 (in experiment 6, the ratio of cells recovered reflected the input ratio). Analysis of the CD4+ T cell response also indicated that HN419–433/Ab-specific T cells from the CD62Llow subset were superior to those from the CD62Lhigh subset in terms of establishing memory, although the absolute numbers were relatively low.

Taken together, the data clearly show that CD62Llow memory T cells respond vigorously to secondary Sendai virus challenge in vivo, both in terms of the absolute numbers of cells recovered, and in the capacity of the cells to migrate to the lung airways. Moreover, the strong expansion of CD62Llow memory T cells occurs in the face of a vigorous response by CD62Lhigh memory T cells. These findings differ from those of Wherry et al. (11) and suggest that the relative contributions of CD62Llow (effector) and CD62Lhigh (central) memory T cells to Sendai virus and LCMV infection may be different. It is possible that this reflects the fact that Sendai virus establishes a mucosal infection, whereas LCMV establishes a systemic infection, even when initially introduced through the nose. However, there are also technical differences in the experiments that may explain the different outcomes. Whereas Wherry et al. (11) used isolated subsets of memory T cells in their transfers, we used blended effector and central memory populations corresponding to the normal memory T cell pool. In addition, we used low numbers of nontransgenic T cells, potentially affecting the level of expansion achieved. Finally, we did not use multimer in the sorting protocol to avoid an affect on the viability or function of the transferred cells.

The finding that CD62Llow effector memory T cells make substantial contributions to recall responses argues against the idea that the primary function of these cells is to immediately engage the pathogen at the site of infection until the central memory T cell population has expanded and produced new effector cells. Rather, it appears that CD62Llow effector memory T cells may be involved in all aspects of the response, including the aggressive generation of new effectors. Given that CD62Llow central memory T cells tend to be excluded from the lymph nodes, this suggests that the reactivation of memory T cell responses in the lung does not necessarily depend on local draining lymph nodes. Indeed, we have shown that strong T cell responses can be initiated in the complete absence of encapsulated lymph nodes (19). Although the data presented in this study demonstrate that CD62Llow memory T cells in the spleen are able to mediate strong recall responses to respiratory virus infections, the proliferative capacity of effector and central memory from other sites is unclear. However, it should be noted that CD62Llow (effector) memory T cells isolated from the lung airways can mediate strong recall responses to secondary challenge (20). In addition, although both effector and central memory T cells expanded vigorously in our studies, we were not able to compare their protective efficacy, because both populations were present in the same animals. Further studies will be required to understand the functional contributions of central and effector memory T cells to secondary respiratory virus challenge.


   Acknowledgments
 
We thank Simon Monard for assistance with flow cytometry; the Molecular Biology Core for producing multimeric reagents; Tres Cookenham for technical help; Drs. Marcy Blackman, Sherry Crowe, Ken Ely, Stephen Smiley, and Iain Scott for critically reviewing the manuscript; and Dr. Larry Johnson for help with the statistics.


   Footnotes
 
1 This work was supported by funds from the Trudeau Institute and the Public Health Service (HL-63925 and HL-69502). Back

2 Address correspondence and reprint requests to Dr. David L. Woodland, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: dwoodland{at}trudeauinstitute.org Back

3 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; BAL, bronchoalveloar lavage; MLN, mediastinal lymph node; NP, nucleoprotein; HN, hemagglutinin-neuraminidase. Back

Received for publication February 24, 2004. Accepted for publication March 26, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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D. M. Catron, L. K. Rusch, J. Hataye, A. A. Itano, and M. K. Jenkins
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T Cell Memory in the Lung Airways
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Differential contributions of central and effector memory T cells to recall responses
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