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Journal of Virology, November 1999, p. 9650-9654, Vol. 73, No. 11
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Requirement for CD40 Ligand, CD4⁺ T Cells, and B Cells in an Infectious Mononucleosis-Like Syndrome

James W. Brooks, Ann Marie Hamilton-Easton, Jan P. Christensen, Rhonda D. Cardin, Charles L. Hardy, and Peter C. Doherty^*

Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Received 5 May 1999/Accepted 22 July 1999

	ABSTRACT

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Respiratory challenge with the murine gammaherpesvirus 68 (HV-68) results in productive infection of the lung, the establishment of latency in B lymphocytes and other cell types, transient splenomegaly, and prolonged clonal expansion of activated CD8⁺ CD62L^lo T cells, particularly a V4⁺ CD8⁺ population that is found in mice with different major histocompatibility complex (MHC) haplotypes. Aspects of the CD8⁺-T-cell response are substantially modified in mice that lack B cells, CD4⁺ T cells, or the CD40 ligand (CD40L). The B-cell-deficient mice show no increase in V4⁺ CD8⁺ T cells. Similar abrogation of the V4⁺ CD8⁺ response is seen following antibody-mediated depletion of the CD4⁺ subset, through the numbers of CD8⁺ CD62L^lo cells are still significantly elevated. Virus-specific CD4⁺-T-cell frequencies are minimal in the CD40L^/ mice, and the V4⁺ CD8⁺ population remains unexpanded. Apparently B-cell-CD4⁺-T-cell interactions play a part in the HV-68 induction of both splenomegaly and non-MHC-restricted V4⁺ CD8⁺-T-cell expansion.

	TEXT

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Infectious mononucleosis (IM) is a debilitating disease of human adolescents (14, 21) induced by the prototypic type 1 gammaherpesvirus (HV), Epstein-Barr virus (EBV). The classical presentation is lymphoid tissue enlargement, concurrent with the presence of large numbers of activated CD8⁺ peripheral blood lymphocytes (PBL). The condition can continue for a month or more. Recent experiments have established that a substantial component of the expanded CD8⁺-T-cell population in the PBL compartment is directed against EBV peptides (5). Much of the IM phase of EBV infection thus reflects the specific host response in lymphoid tissue to this persistent virus.

Experimental dissection (28) of an apparently comparable syndrome induced by intranasal (i.n.) exposure to a type 2 HV, the murine gammaherpesvirus 68 (HV-68), has shown that the onset of the IM-like expansion of activated (CD62L^lo) CD8⁺ T lymphocytes in the blood follows the development of CD4⁺-T-cell-dependent splenomegaly (17, 29). Both the splenic enlargement and the massive increase in CD8⁺-T-cell numbers, particularly a prominent non-major histocompatibility complex (MHC)-restricted CD8⁺ set (28) that expresses the V4 T-cell receptor (TCR), are detected subsequent to immune control (17) of the initial, lytic infection in respiratory epithelium (7). The delay in onset of the IM-like disease suggests that the driving force is persistent, latent HV-68, which can be detected consistently in a small proportion of B lymphocytes by infectious-center assay.

Neither the splenomegaly nor the IM-like syndrome was seen in CD4⁺-T-cell-deficient mice that are homozygous for disruption (/) of the H-2I-A^b MHC class II gene, though the extent of viral latency detected by the infectious-center assay was at least as high as that found for the MHC class II^+/+ controls (7, 10). Also, the HV-68 peptide-specific CD8 response (24) in these MHC class II^/ mice was not obviously diminished (23). Early depletion of CD4⁺ T cells by treating MHC class II^+/+ mice with a subset-specific monoclonal antibody (MAb) prevented the development of splenomegaly, but the IM-like phase had not been recognized at the time of these experiments (29). Giving such a MAb later (from day 11) in the course of HV-68 infection diminished the numbers of cycling CD8⁺ T cells in the PBL, though the frequencies of both the CD8⁺ CD62L^lo and CD8⁺ V4⁺ sets were comparable to those in undepleted mice (28).

The present analysis focused on the role of the CD4⁺ subset in this IM-like disease. The part played by B lymphocytes (26) was also addressed by using immunoglobulin-deficient (Ig^/) µMT mice (15), which lack virus-infected cells that can readily be demonstrated by the infectious center assay (30). However, a further focus of HV-68 latency has now been detected in the macrophage compartment by a different technique (33), and it is clear that µMT mice are indeed persistently infected with HV-68 to the extent that they will die following simultaneous depletion of both CD4⁺ and CD8⁺ T cells (8) long after the acute phase of the infection has been controlled.

Experimental procedures. The methods used here have been described previously and are appropriately referenced throughout the text. The general protocol was to infect anaesthetized, 6- to 10-week-old, female C57BL/6J(B6) and (B6 × 129)F₁ (Ig^+/+ CD40L^+/+), µMT (Ig^/), or CD40L^/ mice (35) i.n. with 600 PFU of HV-68 (7). The µMT mice (15) were bred (with permission from Werner Müller) at St. Jude Children's Research Hospital, while all other mice were purchased from the Jackson Laboratory (Bar Harbor, Maine). The mice were anaesthetized again at the time of sampling, when PBL and spleen populations were obtained for flow cytometric analysis (28) and the lung and lymphoid compartments were assayed for the presence of lytic (lung) and latent (spleen and lymph nodes) virus (6, 7). Frequencies of virus-specific CD4⁺ T cells were determined by the gamma interferon (IFN-) ELISpot assay (9). The prevalence of virus-specific CD8⁺ T cells (23, 24) was assessed by stimulating cells for 6 h with HV-68 peptide in the presence of brefeldin A and then staining for IFN- and analyzing in a FACScan by using CellQuest software (Becton Dickinson, San Jose, Calif.). Lymphocyte phenotypes were determined (28) by staining with phycoerythrin (PE)- or fluorescein isothiocyanate (FITC)-conjugated MAbs (all supplied by Pharmingen, San Diego, Calif.) specific for CD4 (RM4-5-PE), CD8 (53-6.72-PE), CD62L (MEL-14-FITC), and V4 TCR (KT4-FITC).

Consequences of B-cell deficiency. Previous experiments established that the Ig^/ µMT mice (15) utilize both CD4⁺ and CD8⁺ T cells to control the acute, lytic phase of HV-68 infection (8), though there has been some debate about the extent of subsequent viral latency (30-32). The present study with i.n. challenged µMT mice also failed to demonstrate persistent HV-68 by the infectious center assay, but the continued presence of HV-68 throughout the lymphoid compartment was confirmed (Table 1) by a primary culture system based on that used previously to demonstrate the presence of cytomegalovirus (6).

View this table: [in this window] [in a new window]   TABLE 1.   Virus persistence in the lymphoid tissue of Ig+/+ and Ig/ micea

The absence of B-cell follicle development in the Ig^/ µMT mice results in a spleen size that is normally about 20% of that detected in the Ig^+/+ controls (27). The relative prevalence of CD4⁺ T cells in the µMT spleen and blood is also decreased (Fig. 1, day 0). Respiratory challenge with HV-68 fails to cause the splenomegaly found in Ig^+/+ B6 mice (30). However, the prevalence of the "activated" CD8⁺ CD62L^lo population (28) was increased in both the Ig^+/+ and Ig^/ groups from day 14 after infection, though the IM-like phase (28) in the µMT mice was diminished in magnitude (Fig. 1B). The essential difference was that the B-cell-deficient Ig^/ mice did not show the characteristic increase in V4⁺ CD8⁺-T-cell numbers for either the spleen (Fig. 2A) or the blood (Fig. 2B).

View larger version (39K): [in this window] [in a new window]   FIG. 1.   Prevalence and activation status of splenic (A) and PBL (B) CD8+ T cells from HV-68-infected B6 and µMT mice. The splenocytes were pooled, while the PBL samples were analyzed for individuals (28). The experiment was done three times; the results are from one representative experiment and are expressed as percents (spleen) or mean percents ± standard deviations (PBL).

View larger version (18K): [in this window] [in a new window]   FIG. 2.   The spectrum of TCR V4 expression on CD8+ T cells from spleen (A) and PBL (B) populations from HV-68 infected B6 and µMT mice. The experiment was done twice, and results of one representative experiment are shown. The values are for pooled samples from four or five mice.

HV-68 infection in CD40L^/ mice. The lack of splenomegaly and V4⁺ CD8⁺ T cell expansion in the µMT mice could be thought to be due to the presence of less persistently infected cells (Table 1), the decreased size of the virus-specific CD4⁺ set, or the absence of B cells. Effective T help for antibody production requires that the CD40 ligand (CD40L) expressed on the CD4⁺ T cell bind the CD40 molecule on the B cell, a recognition event that induces efficient activation of both cell types (2, 11, 13, 16, 18, 20, 22). Experiments with CD40L^/ mice (20, 35) have established the importance of this interaction in several different virus infections (3, 4, 12, 19, 34).

Following respiratory challenge with HV-68, the CD40L^/ mice showed some of the changes described previously for the CD4⁺-T-cell-deficient MHC class II^/ mice (7). Though the lytic phase of virus growth was to some extent controlled in the respiratory tract, evidence of productive infection in this site continued in the long term (Fig. 3A). Furthermore, unlike the situation for the µMT mice (Table 1), evidence of viral latency was readily demonstrated by the infectious-center assay (Fig. 3B). Also, as with the MHC class II^/ mice (23), the magnitude of the CD8⁺-T-cell response to the p56 and p79 peptides of HV-68 was essentially normal in the absence of the CD40-CD40L interaction (Table 2). The virus-specific CD4⁺-T-cell response detected by the ELISpot assay was, however, substantially absent from the CD40L^/ group (Table 2).

View larger version (25K): [in this window] [in a new window]   FIG. 3.   Levels of replicating and latent HV-68 virus in (B6 × 129)F1 and CD40L/ mice. The titers (7) of infectious virus in lung (A) and the extent of viral latency in the spleen (B) are given as means ± standard deviations. The titers of lytic virus in spleen cells that were disrupted before plating were generally <1 PFU/107 cells. The results given are from two separate sets of observations, with three or four mice per time point in each experiment.

View this table: [in this window] [in a new window]   TABLE 2.   Virus-specific T-cell responses in CD40L/ and (B6 × 129)F1 micea

The prevalence of activated CD8⁺ CD62L^lo cells tended to be lower but, in the groups of three to six mice used in these experiments, was not significantly different from that found for the CD40L^+/+ controls (data not shown). However, the prominent V4⁺ CD8⁺-T-cell response that occurs in conventional mice (28) was completely abrogated by the absence of the CD40L (Fig. 4). Furthermore, the elimination of the CD4⁺ subset by treating the (B6 × 129)F₁ mice with a MAb to CD4 from the time of infection (1) also prevented the expansion of the V4⁺ CD8⁺ set (Fig. 4), though the prevalence of CD8⁺ CD62L^lo cells in the spleen and PBL compartments of such mice was consistently above the levels found in the naive controls (Fig. 5).

View larger version (20K): [in this window] [in a new window]   FIG. 4.   Expression of the V4 TCR on CD8+ T cells in the PBL population. Some of the HV-68-infected (B6 × 129)F1 and CD40L/ mice were treated from 2 days before virus challenge with successive doses of the GK1.5 MAb, a procedure that effectively eliminates the CD4+ subset (1). The experiment was done twice, with results of one representative experiment being shown. The results are means ± standard deviations for three or four individuals.

View larger version (21K): [in this window] [in a new window]   FIG. 5.   Activation status of splenic (A) and PBL (B) CD8+ T cells in HV-68-infected intact or CD4-depleted (Fig. 4) B6 mice. The results are means ± standard deviations for a representative experiment (28). The total number of activated CD8+ T cells (A) was derived by multiplying the cell count for the spleen by the percent CD8+ CD62Llo cells. With the exception of the findings for the CD4-depleted PBL population assayed on day 12, all values shown in both panels for the HV-68-infected mice are significantly greater (P < 0.05) than those for the uninfected controls (day 0). The experiment was done three times, with results of one representative experiment being shown.

Conclusions. The experiments with the CD4-depleted and CD40L^/ mice establish that CD4⁺ T cells are required to promote the expansion of V4⁺ CD8⁺ T cells that is so characteristic of HV-68 infection (28). The virus-specific CD8⁺-T-cell response does not, however, seem to depend on CD4⁺ T help, and the prevalence of CD8⁺ CD62L^lo T cells in the spleen and PBL is still increased in the absence of the CD4⁺ subset. The same profile is seen in the absence of B cells, though the Ig^/ µMT mice make an effective CD4⁺-T-cell response that can control persistent HV-68 infection by an IFN--dependent process (8).

The obvious conclusion is that the CD4⁺ helpers induce some modification of the B-cell surface that stimulates the V4⁺ CD8⁺ T cells. The CD4⁺-T-cell depletion experiments indicate that this event must occur during the acute phase of the host response (Fig. 4 and 5), prior to day 11 (28). It is not known whether the entity recognized by this unusual non-MHC-restricted V4⁺ CD8⁺ set is encoded by the virus or is some aberrantly expressed self component. Apart from the fact that T-cell help is required for both the massive HV-68-induced, nonspecific IgG response and for the production of virus-specific antibody (25), we currently know very little about the interaction between CD4⁺ T cells and B cells in this infection.

	ACKNOWLEDGMENTS

This work was supported by the Public Health Service grants CA90436, CA21765, and AI38359 and by the American Lebanese-Syrian Associated Charities. J.P.C. is the recipient of a fellowship from the Alfred Benzons Foundation, Denmark.

We thank Suzette Wingo, Phuong Nguyen, Kris Branum, and Mhedi Mehrpooya for technical assistance.

	FOOTNOTES

^* Corresponding author. Mailing address: Department of Immunology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-3470. Fax: (901) 495-3107. E-mail: peter.doherty{at}stjude.org.

Present address: Transduction Laboratories, Inc., Lexington, KY 40511.

Present address: Infectious Diseases, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48103.

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Journal of Virology, November 1999, p. 9650-9654, Vol. 73, No. 11
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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