HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Varga, S. M. Articles by Welsh, R. M. Search for Related Content PubMed PubMed Citation Articles by Varga, S. M. Articles by Welsh, R. M. Pubmed/NCBI databases Substance via MeSH

Cutting Edge: Detection of a High Frequency of Virus-Specific CD4⁺ T Cells During Acute Infection with Lymphocytic Choriomeningitis Virus¹

Department of Pathology, University of Massachusetts Medical Center, Worcester, MA 01655

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Lymphocytic choriomeningitis virus (LCMV), like many viruses, induces a profound activation and expansion of CD8⁺ T cells. In contrast, CD4⁺ T cells do not increase in total number during the acute infection. We show here that mice infected with LCMV have a low but detectable frequency (<1/300) of CD4⁺ T cells, as detected by IL-2 production in limiting dilution assays, to each of two class II peptides during the peak of the acute LCMV response and into long-term memory. However, during the peak of the acute CD4⁺ T cell response, >20% of the CD4⁺ T cells secreted IFN- after stimulation with PMA and ionomycin, and >10% of the CD4⁺ T cells secreted IFN- after stimulation with the LCMV peptides. Thus, these new sensitive assays reveal a heretofore unappreciated, yet profound Ag-specific CD4⁺ T cell response during viral infections.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Virus infections are potent stimulators of the immune system (1, 2, 3). During an acute lymphocytic choriomeningitis virus (LCMV)³ infection, the CD8⁺ T cells expand as much as 5- to 10-fold, resulting in a conversion of the CD4 to CD8 ratio from 2:1 to 1:2–3 (4). Coincident with this expansion is an increase in the frequency of virus-specific CTL precursors as detected by limiting dilution analysis (LDA) (5, 6). However, either due to a low efficiency or because a low percentage of Ag-specific cells are cytotoxic, LDA only accounts for a small fraction (5–10%) of the activated CD8⁺ T cells during the acute LCMV infection (6, 7). Nevertheless, because there is little expansion in the number of T cells not specific to the virus during infection (8), we have concluded that the great majority of activated cells during LCMV infection is virus specific. A similar conclusion has been reached in recent studies using MHC class I tetramers loaded with immunodominant viral peptides and intracellular staining for IFN- following virus-peptide stimulation (9, 10, 11). These techniques can now account for nearly 70% of the CD8⁺ T cells that respond during an acute LCMV infection (9).

Although usually not as vigorously stimulated as CD8⁺ T cells, CD4⁺ T cells also become activated and respond during acute viral infections (1). In the LCMV system, about 25% of the CD4⁺ T cells are blast-sized at day 7 postinfection (p.i.). In addition, 20 to 30% of the CD4⁺ T cells express increased cell surface levels of activation markers and adhesion molecules (12, 13, 14). Thus, a significant percentage of the CD4⁺ T cells are activated during the acute LCMV infection, but <1% of these cells scored in LDA as being virus specific (13). Here we show, by using a sensitive assay to measure IFN- production at the single cell level, that >10% of the CD4⁺ T cells are virus specific during an acute LCMV infection.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Infection of mice and preparation of spleen cells

Male C57BL/6 (H-2^b) mice from The Jackson Laboratory (Bar Harbor, ME) were inoculated i.p. with 7 x 10⁴ plaque-forming units of LCMV, Armstrong strain, diluted 1:100 in PBS in 0.1 ml vol/mouse. Splenic leukocytes were obtained by preparing single-cell suspensions from spleens and treating them with 0.84% NH₄Cl to lyse E (15). For CD4⁺ T cell cycle analysis, splenic leukocytes were stained with FITC-conjugated anti-CD4 (H129.19) from PharMingen (San Diego, CA). After washing in staining buffer (2% FCS and 0.02% NaN₃ in PBS), the cells were subsequently fixed in ice-cold 95% ethanol, washed in PBS, and stained with propidium iodide (Sigma, St. Louis, MO). Approximately 1 x 10⁶ cells were stained, and >20,000 events were acquired from each preparation. The data were analyzed using Cell Quest software (Becton Dickinson, San Jose, CA).

Cell sorting and Th precursor (Thp) frequency analysis

The LDA for determining LCMV-specific CD4⁺ Thp frequency has been described previously in detail (13). To determine the frequency of peptide-specific Thp, peritoneal exudate cells (PEC) were pulsed with 5 µg/ml of one of the two known LCMV class II-restricted peptides, GP61-80 and NP309-328 (16). Frequencies were calculated using ² analysis according to the method of Taswell (17) on a computer program kindly provided by Dr. Richard Miller (University of Michigan, Ann Arbor, MI).

Intracellular IFN- staining

Intracellular IFN- staining was performed based on modifications of recently published protocols (9, 18). To assess intracellular cytokine expression in cells activated nonspecifically, 2 x 10⁶ spleen cells were cultured for 4 h in 50 ng/ml of PMA (Sigma) and 500 ng/ml of ionomycin (Sigma), with 10 µg/ml of Brefeldin A (Sigma) added for the final 2 h to enable intracellular proteins to accumulate. For Ag-specific expression of cytokines, splenocytes were cultured for 5 h at a concentration of 2 x 10⁶ cells/tube in a volume of 1 ml of complete medium supplemented with 10 U/ml of recombinant mouse IL-2 (PharMingen) and 10 µg/ml of Brefeldin A in the presence (5 µg/ml) or absence of one of the two LCMV peptides. After 5-h culture, the cells were harvested, washed once in staining buffer, blocked with purified anti-FcRII/III mAb (2.4G2; PharMingen) for 10 min on ice, and surface stained with either FITC-conjugated anti-CD4 (H129.19; PharMingen) or tricolor-conjugated anti-CD4 (CT-CD4; Caltag, Burlingame, CA) for 30 min on ice. In some experiments, the cells were also stained with FITC-conjugated anti-CD44 (IM7; PharMingen). The cells were then washed in staining buffer and fixed with 2% formaldehyde in PBS for 20 min at room temperature. Following two washes with permeabilization buffer (staining buffer containing 0.5% saponin, Sigma), the cells were resuspended in 100 µl of permeabilization buffer and incubated for 10 min at room temperature, followed by an additional 30-min incubation after the addition of phycoerythrin conjugated anti-mouse IFN- (XMG1.2; PharMingen) or an isotype control (IgG1; PharMingen). Cells treated with PMA and ionomycin were also stained with FITC-conjugated anti-mouse IL-4 (BVD4-1D11; PharMingen) or the appropriate isotype control (IgG2b; PharMingen). Approximately 2 x 10⁶ cells were stained, and between 30,000 and 60,000 events were acquired from each sample. The data were analyzed using Cell Quest software (Becton Dickinson).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Quantitation of the peptide-specific CD4⁺ Thp

Table I shows the Thp frequencies for the two known LCMV class II-restricted peptides (16) during the peak of the acute CD4⁺ T cell response and into long-term memory. The stability of the virus-specific Thp frequencies up to 18 mo p.i. following stimulation with LCMV-infected PEC shown here extends on our previous work regarding the stability of CD4⁺ Thp frequencies into long-term memory (13). The Thp frequency to each of the two LCMV class II-restricted peptides dropped only 2- to 7-fold from the peak of the CD4⁺ T cell response into memory (Table I). Quantitation of virus-specific Thp frequencies using this established LDA method for IL-2 in several virus systems has yielded Thp frequencies that range from 1/300 to 1/2000 from the peak of the acute response into long-term memory (13, 19, 20, 21). Thus, <1% of the CD4⁺ T cells can be identified by LDA as Ag specific during these infections.

Although the total CD4⁺ T cell number remains relatively stable during the acute LCMV infection, there is an increase in the percentage of blast-sized CD4⁺ T cells and of CD4⁺ T cells expressing various activation and adhesion molecules (13). Using enzyme-linked immunospot (ELISPOT) assays (in the absence of added IL-2) to assess IFN- production at the single-cell level, we previously found that the frequency of sorted CD4⁺ T cells that produced IFN- when stimulated with LCMV-infected PEC was similar to the Thp frequency in the IL-2-based LDA (13). In contrast, Figure 1 shows that a much higher frequency (>20%) of CD4⁺ T cells from mice acutely infected with LCMV make IFN- when nonspecifically stimulated with PMA and ionomycin. We find no increase in the percentage of IL-4-producing CD4⁺ T cells during the acute LCMV infection, confirming that LCMV induces primarily a Th1 response (13, 22, 23). Analysis of DNA content by propidium iodide staining revealed an increase in the percentage of CD4⁺ T cells in the cell cycle. The mean percentages of CD4⁺ T cells in G₂ + M or S phase from six individual mice per group were as follows: day 0, 2 ± 1%; day 7, 7 ± 2%, day 9, 6 ± 2%; day 11, 5 ± 1%; 7 mo, 2 ± 1%; 11 mo, 2 ± 1%; 19 mo, 2 ± 1%. Thus, there is a much larger percentage of CD4⁺ T cells that are expressing an activated cell phenotype, that are blast-sized and have entered the cell cycle, and that produce IFN- on stimulation, than can be accounted for by using LDA (Table I and 13 .

View larger version (23K): [in this window] [in a new window]   FIGURE 1. Intracellular IFN- and IL-4 expression of virus-induced CD4+ T cells following stimulation with PMA and ionomycin. Splenocytes from the indicated days postinfection were stimulated with PMA and ionomycin for 2 h before the addition of Brefeldin A for an additional 2 h as described in Materials and Methods. The cells were gated on CD4+ cells, and the values shown represent the percentage of CD4+ cells that expressed a given cytokine. Means ± SDs for time points from two separate experiments with two individual mice per experiment are shown (n = 4/group).

Intracellular staining of peptide-specific IFN--producing CD4⁺ T cells

The above experiments show that at least 20 to 25% of the CD4⁺ T cells produce IFN- when nonspecifically stimulated with PMA and ionomycin during the acute LCMV infection. The peptide-specific intracellular IFN- assay, displayed in Figure 2, shows that >10% of the CD4⁺ T cells at day 9 p.i. were specific for either of two class II-restricted peptides. CD4⁺ T cells produced no IFN- in the absence of peptide, and peptide-stimulated CD4⁺ T cells did not demonstrate any intracellular staining above background with the isotype control Ab. Figure 3 shows that virtually all of the GP61-80-specific CD4⁺ T cells that stained positive for IFN- were also CD44^high, consistent with an activated cell phenotype (24). Figure 4 shows a time course in which the IFN--producing cells peak at day 9 p.i. but are still detectable in long-term memory.

View larger version (42K): [in this window] [in a new window]   FIGURE 2. Intracellular IFN- expression of LCMV peptide-specific CD4+ T cells. Splenocytes from LCMV-infected (day 9) C57BL/6 mice were stimulated with or without one of the two LCMV class II-restricted peptides in the presence of IL-2 and Brefeldin A for 5 h as described in Materials and Methods. The numbers shown indicate the percentage of cells that fall into each gate. Data are representative of four experiments.

View larger version (30K): [in this window] [in a new window]   FIGURE 3. CD44 expression on peptide-specific CD4+ T cells staining positive for intracellular IFN-. Splenocytes from LCMV-infected (day 9) mice were cultured in vitro with GP61-80 in the presence of IL-2 and Brefeldin A for 5 h as described in Materials and Methods. Top panel, numbers shown in the R1 gate indicate the percentage of splenocytes that are positive for the A isotype control mAb, B intracellular IFN- stain, or C control IFN- staining of cells from day 9-infected mice prestained with unlabeled anti-IFN- mAb. The histograms in the bottom panel (D and E) represent the cell surface expression of CD44 on the two gated populations from B. Data are representative of four separate experiments.

View larger version (21K): [in this window] [in a new window]   FIGURE 4. Intracellular IFN- expression of LCMV peptide-specific CD4+ T cells. Splenocytes from the indicated days postinfection were stimulated with one of the two LCMV class II-restricted peptides in the presence of IL-2 and Brefeldin A for 5 h as described in Materials and Methods. Background staining with the appropriate isotype-matched control mAb was subtracted from each individual. Means ± SDs for time points from four separate experiments with two individual mice per experiment are shown (n = 8/group).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

In the present study with sensitive assays to measure IFN- production at the single-cell level, >20% of the CD4⁺ T cells secreted IFN- after stimulation with PMA and ionomycin, and >10% of the CD4⁺ T cells secreted IFN- after stimulation with the LCMV peptides. The discrepancy between these two numbers could be accounted for either by PMA and ionomycin stimulation detecting lower affinity responses or responses specific to undefined virus-encoded class II peptides. This discrepancy could also be due to a nonspecific bystander activation of CD4⁺ T cells, although this would seem unlikely based on other studies directly examining bystander activation (8).

	Acknowledgments

 
We thank C. Kamperschroer for his helpful suggestions, Keith Daniels for his technical assistance, and Tammy Krumpoch and Barbara Fournier for help with the FACS analysis.

	Footnotes

 
¹ This work was supported by U.S. Public Health Service Training Grant AI07439 to S.M.V. and by Research Grants AI17672 and AR35506 to R.M.W.

² Address correspondence and reprint requests to Dr. Raymond M. Welsh, Department of Pathology, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, MA 01655. E-mail address:

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; LDA, limiting dilution analysis; Thp, Th precursor; PEC, peritoneal exudate cell; p.i., postinfection.

Received for publication June 22, 1998. Accepted for publication August 3, 1998.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Doherty, P. C., D. J. Topham, R. A. Tripp. 1996. Establishment and persistence of virus-specific CD4⁺ and CD8⁺ T cell memory. Immunol. Rev. 150:23.[Medline]
2. Zinkernagel, R. M.. 1996. Immunology taught by viruses. Science 271:173.[Abstract]
3. Ahmed, R., D. Gray. 1996. Immunological memory and protective immunity: understanding their relation. Science 272:54.[Abstract]
4. Selin, L. K., R. M. Welsh. 1994. Specificity and editing by apoptosis of virus-induced cytotoxic T lymphocytes. Curr. Opin. Immunol. 6:553.[Medline]
5. Assmann-Wischer, U., D. Moskophidis, M. M. Simon, F. Lehmann-Grube. 1986. Numbers of cytolytic T lymphocytes (CTL) and CTL precursor cells in spleens of mice acutely infected with lymphocytic choriomeningitis virus. Med. Microbiol. Immunol. 175:141.[Medline]
6. Selin, L. K., K. Vergilis, R. M. Welsh, S. R. Nahill. 1996. Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections. J. Exp. Med. 183:2489.[Abstract/Free Full Text]
7. Lau, L. L., B. D. Jamieson, T. Somasundaram, R. Ahmed. 1994. Cytotoxic T-cell memory without antigen. Nature 369:648.[Medline]
8. Zarozinski, C. C., R. M. Welsh. 1997. Minimal bystander activation of CD8 T cells during the virus-induced polyclonal T cell response. J. Exp. Med. 185:1629.[Abstract/Free Full Text]
9. Murali-Krishna, K., J. D. Altman, M. Suresh, D. J. D. Sourdive, A. J. Zajac, J. D. Miller, J. Slansky, R. Ahmed. 1998. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8:177.[Medline]
10. Butz, E. A., M. J. Bevan. 1998. Massive expansion of antigen-specific CD8⁺ T cells during an acute virus infection. Immunity 8:167.[Medline]
11. Gallimore, A., A. Glithero, A. Godkin, A. C. Tissot, A. Pluckthun, T. Elliott, H. Hengartner, R. Zinkernagel. 1998. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J. Exp. Med. 187:1383.[Abstract/Free Full Text]
12. Varga, S. M., R. M. Welsh. 1996. The CD45RB-associated epitope defined by monoclonal antibody CZ-1 is an activation and memory marker for mouse CD4 T cells. Cell. Immunol. 167:56.[Medline]
13. Varga, S. M., R. M. Welsh. 1998. Stability of virus-specific CD4⁺ T cell frequencies from acute infection into long term memory. J. Immunol. 161:367.[Abstract/Free Full Text]
14. Whitmire, J. K., M. A. Slifka, I. S. Grewal, R. A. Flavell, R. Ahmed. 1996. CD40 ligand-deficient mice generate a normal primary cytotoxic T-lymphocyte response but a defective humoral response to a viral infection. J. Virol. 70:8375.[Abstract]
15. McFarland, H. I., S. R. Nahill, J. W. Maciaszek, R. M. Welsh. 1992. CD11b (Mac-1): A marker for CD8⁺ cytotoxic T cell activation and memory in virus infection. J. Immunol. 149:1326.[Abstract]
16. Oxenius, A., M. F. Bachmann, P. G. Ashton-Rickardt, S. Tonegawa, R. M. Zinkernagel, H. Hengartner. 1995. Presentation of endogenous viral proteins in association with major histocompatibility complex class II: on the role of intracellular compartmentalization, invariant chain and the TAP transporter system. Eur. J. Immunol. 25:3402.[Medline]
17. Taswell, C.. 1981. Limiting dilution assays for the determination of immunocompetent cell frequencies I. Data analysis. J. Immunol. 126:1614.[Abstract]
18. Openshaw, P., E. E. Murphy, N. A. Hosken, V. Maino, K. Davis, K. Murphy, A. O’Garra. 1995. Heterogeneity of intracellular cytokine synthesis at the single-cell level in polarized T helper 1 and T helper 2 populations. J. Exp. Med. 182:1357.[Abstract/Free Full Text]
19. Ewing, C., D. J. Topham, P. C. Doherty. 1995. Prevalence and activation phenotype of Sendai virus-specific CD4⁺ T cells. Virology 210:179.[Medline]
20. Topham, D. J., R. A. Tripp, A. M. Hamilton-Easton, S. R. Sarawar, P. C. Doherty. 1996. Quantitative analysis of the influenza virus-specific CD4⁺ T cell memory in the absence of B cells and Ig. J. Immunol. 157:2947.[Abstract]
21. Tripp, R. A., D. J. Topham, S. R. Watson, P. C. Doherty. 1997. Bone marrow can function as a lymphoid organ during a primary immune response under conditions of disrupted lymphocyte trafficking. J. Immunol. 158:3716.[Abstract]
22. Oxenius, A., K. A. Campbell, C. R. Maliszewski, T. Kishimoto, H. Kikutani, H. Hengartner, R. M. Zinkernagel, M. F. Bachmann. 1996. CD40-CD40 ligand interactions are critical in T-B cooperation but not for other anti-viral CD4⁺ T cell functions. J. Exp. Med. 183:2209.[Abstract/Free Full Text]
23. Su, H. C., L. P. Cousens, L. D. Fast, M. K. Slifka, R. D. Bungiro, R. Ahmed, C. A. Biron. 1998. CD4⁺ and CD8⁺ T cell interactions in IFN- and IL-4 responses to viral infections: requirements for IL-2. J. Immunol. 160:5007.[Abstract/Free Full Text]
24. Bradley, L. M., M. Croft, S. L. Swain. 1993. T-cell memory: new perspectives. Immunol. Today 14:197.[Medline]
25. Kasaian, M., K. A. Leite-Morris, C. A. Biron. 1991. The role of CD4⁺ cells in sustaining lymphocyte proliferation during lymphocytic choriomeningitis virus infection. J. Immunol. 146:1955.[Abstract]

This article has been cited by other articles:

				M. O. Seedhom, E. R. Jellison, K. A. Daniels, and R. M. Welsh High Frequencies of Virus-Specific CD8+ T-Cell Precursors J. Virol., December 15, 2009; 83(24): 12907 - 12916. [Abstract] [Full Text] [PDF]

				S. Z. Ben-Sasson, J. Hu-Li, J. Quiel, S. Cauchetaux, M. Ratner, I. Shapira, C. A. Dinarello, and W. E. Paul IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation PNAS, April 28, 2009; 106(17): 7119 - 7124. [Abstract] [Full Text] [PDF]

				K. S. Mathurin, G. W. Martens, H. Kornfeld, and R. M. Welsh CD4 T-Cell-Mediated Heterologous Immunity between Mycobacteria and Poxviruses J. Virol., April 15, 2009; 83(8): 3528 - 3539. [Abstract] [Full Text] [PDF]

				C. Fang, T. Miwa, H. Shen, and W.-C. Song Complement-Dependent Enhancement of CD8+ T Cell Immunity to Lymphocytic Choriomeningitis Virus Infection in Decay-Accelerating Factor-Deficient Mice J. Immunol., September 1, 2007; 179(5): 3178 - 3186. [Abstract] [Full Text] [PDF]

				B. R. Mothe, B. S. Stewart, C. Oseroff, H.-H. Bui, S. Stogiera, Z. Garcia, C. Dow, M. P. Rodriguez-Carreno, M. Kotturi, V. Pasquetto, et al. Chronic Lymphocytic Choriomeningitis Virus Infection Actively Down-Regulates CD4+ T Cell Responses Directed against a Broad Range of Epitopes J. Immunol., July 15, 2007; 179(2): 1058 - 1067. [Abstract] [Full Text] [PDF]

				L. H. Hogan, D. O. Co, J. Karman, E. Heninger, M. Suresh, and M. Sandor Virally Activated CD8 T Cells Home to Mycobacterium bovis BCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice Infect. Immun., March 1, 2007; 75(3): 1154 - 1166. [Abstract] [Full Text] [PDF]

				K. Bahl, S.-K. Kim, C. Calcagno, D. Ghersi, R. Puzone, F. Celada, L. K. Selin, and R. M. Welsh IFN-Induced Attrition of CD8 T Cells in the Presence or Absence of Cognate Antigen during the Early Stages of Viral Infections J. Immunol., April 1, 2006; 176(7): 4284 - 4295. [Abstract] [Full Text] [PDF]

				J. K. Whitmire, N. Benning, and J. L. Whitton Precursor Frequency, Nonlinear Proliferation, and Functional Maturation of Virus-Specific CD4+ T Cells. J. Immunol., March 1, 2006; 176(5): 3028 - 3036. [Abstract] [Full Text] [PDF]

				D. G. Brooks, L. Teyton, M. B. A. Oldstone, and D. B. McGavern Intrinsic Functional Dysregulation of CD4 T Cells Occurs Rapidly following Persistent Viral Infection J. Virol., August 15, 2005; 79(16): 10514 - 10527. [Abstract] [Full Text] [PDF]

				S.-K. Kim, M. Cornberg, X. Z. Wang, H. D. Chen, L. K. Selin, and R. M. Welsh Private specificities of CD8 T cell responses control patterns of heterologous immunity J. Exp. Med., February 22, 2005; 201(4): 523 - 533. [Abstract] [Full Text] [PDF]

				F. Y. Yue, C. M. Kovacs, R. C. Dimayuga, X. X. J. Gu, P. Parks, R. Kaul, and M. A. Ostrowski Preferential Apoptosis of HIV-1-Specific CD4+ T Cells J. Immunol., February 15, 2005; 174(4): 2196 - 2204. [Abstract] [Full Text] [PDF]

				E. R. Jellison, S.-K. Kim, and R. M. Welsh Cutting Edge: MHC Class II-Restricted Killing In Vivo during Viral Infection J. Immunol., January 15, 2005; 174(2): 614 - 618. [Abstract] [Full Text] [PDF]

				A. E. Williams, L. Edwards, I. R. Humphreys, R. Snelgrove, A. Rae, R. Rappuoli, and T. Hussell Innate Imprinting by the Modified Heat-Labile Toxin of Escherichia coli (LTK63) Provides Generic Protection against Lung Infectious Disease J. Immunol., December 15, 2004; 173(12): 7435 - 7443. [Abstract] [Full Text] [PDF]

				A. Srinivasan, J. Foley, and S. J. McSorley Massive Number of Antigen-Specific CD4 T Cells during Vaccination with Live Attenuated Salmonella Causes Interclonal Competition J. Immunol., June 1, 2004; 172(11): 6884 - 6893. [Abstract] [Full Text] [PDF]

				T. J. Roberts, Y. Lin, P. M. Spence, L. Van Kaer, and R. R. Brutkiewicz CD1d1-Dependent Control of the Magnitude of an Acute Antiviral Immune Response J. Immunol., March 15, 2004; 172(6): 3454 - 3461. [Abstract] [Full Text] [PDF]

				S.-K. Kim and R. M. Welsh Comprehensive Early and Lasting Loss of Memory CD8 T Cells and Functional Memory during Acute and Persistent Viral Infections J. Immunol., March 1, 2004; 172(5): 3139 - 3150. [Abstract] [Full Text] [PDF]

				N. H. Shoukry, J. Sidney, A. Sette, and C. M. Walker Conserved Hierarchy of Helper T Cell Responses in a Chimpanzee during Primary and Secondary Hepatitis C Virus Infections J. Immunol., January 1, 2004; 172(1): 483 - 492. [Abstract] [Full Text] [PDF]

				C. D. Peacock, S.-K. Kim, and R. M. Welsh Attrition of Virus-Specific Memory CD8+ T Cells During Reconstitution of Lymphopenic Environments J. Immunol., July 15, 2003; 171(2): 655 - 663. [Abstract] [Full Text] [PDF]

				B. M. Naiman, S. Blumerman, D. Alt, C. A. Bolin, R. Brown, R. Zuerner, and C. L. Baldwin Evaluation of Type 1 Immune Response in Naive and Vaccinated Animals following Challenge with Leptospira borgpetersenii Serovar Hardjo: Involvement of WC1+{gamma}{delta} and CD4 T Cells Infect. Immun., November 1, 2002; 70(11): 6147 - 6157. [Abstract] [Full Text] [PDF]

				M. Sester, U. Sester, B. C. Gartner, M. Girndt, A. Meyerhans, and H. Kohler Dominance of Virus-Specific CD8 T Cells in Human Primary Cytomegalovirus Infection J. Am. Soc. Nephrol., October 1, 2002; 13(10): 2577 - 2584. [Abstract] [Full Text] [PDF]

				M. H. Yen, N. Lepak, and S. L. Swain Induction of CD4 T Cell Changes in Murine AIDS Is Dependent on Costimulation and Involves a Dysregulation of Homeostasis J. Immunol., July 15, 2002; 169(2): 722 - 731. [Abstract] [Full Text] [PDF]

				S.-K. Kim, M. A. Brehm, R. M. Welsh, and L. K. Selin Dynamics of Memory T Cell Proliferation Under Conditions of Heterologous Immunity and Bystander Stimulation J. Immunol., July 1, 2002; 169(1): 90 - 98. [Abstract] [Full Text] [PDF]

				M. Sester, U. Sester, B. Gartner, B. Kubuschok, M. Girndt, A. Meyerhans, and H. Kohler Sustained High Frequencies of Specific CD4 T Cells Restricted to a Single Persistent Virus J. Virol., March 19, 2002; 76(8): 3748 - 3755. [Abstract] [Full Text] [PDF]

				A. Nansen, J. P. Christensen, S. O. Andreasen, C. Bartholdy, J. E. Christensen, and A. R. Thomsen The role of CC chemokine receptor 5 in antiviral immunity Blood, February 15, 2002; 99(4): 1237 - 1245. [Abstract] [Full Text] [PDF]

				M. G. von Herrath, T. Wolfe, U. Mohrle, B. Coon, and A. Hughes Protection From Type 1 Diabetes in the Face of High Levels of Activated Autoaggressive Lymphocytes in a Viral Transgenic Mouse Model Crossed to the SV129 Strain Diabetes, December 1, 2001; 50(12): 2700 - 2708. [Abstract] [Full Text] [PDF]

				F. Rodriguez, S. Harkins, J. M. Redwine, J. M. de Pereda, and J. L. Whitton CD4+ T Cells Induced by a DNA Vaccine: Immunological Consequences of Epitope-Specific Lysosomal Targeting J. Virol., November 1, 2001; 75(21): 10421 - 10430. [Abstract] [Full Text] [PDF]

				M. Villalba, K. Bi, F. Rodriguez, Y. Tanaka, S. Schoenberger, and A. Altman Vav1/Rac-dependent actin cytoskeleton reorganization is required for lipid raft clustering in T cells J. Cell Biol., October 29, 2001; 155(3): 331 - 338. [Abstract] [Full Text] [PDF]

				L. K. Selin, P. A. Santolucito, A. K. Pinto, E. Szomolanyi-Tsuda, and R. M. Welsh Innate Immunity to Viruses: Control of Vaccinia Virus Infection by {{gamma}}{{delta}} T Cells J. Immunol., June 1, 2001; 166(11): 6784 - 6794. [Abstract] [Full Text] [PDF]

				S. Nikiforow, K. Bottomly, and G. Miller CD4+ T-Cell Effectors Inhibit Epstein-Barr Virus-Induced B-Cell Proliferation J. Virol., April 15, 2001; 75(8): 3740 - 3752. [Abstract] [Full Text]

				J. S. Haring, L. L. Pewe, and S. Perlman High-Magnitude, Virus-Specific CD4 T-Cell Response in the Central Nervous System of Coronavirus-Infected Mice J. Virol., March 15, 2001; 75(6): 3043 - 3047. [Abstract] [Full Text]

				A. Ciurea, L. Hunziker, P. Klenerman, H. Hengartner, and R. M. Zinkernagel Impairment of Cd4+ T Cell Responses during Chronic Virus Infection Prevents Neutralizing Antibody Responses against Virus Escape Mutants J. Exp. Med., February 5, 2001; 193(3): 297 - 306. [Abstract] [Full Text] [PDF]

				S. M. Varga, L. K. Selin, and R. M. Welsh Independent Regulation of Lymphocytic Choriomeningitis Virus-Specific T Cell Memory Pools: Relative Stability of CD4 Memory Under Conditions of CD8 Memory T Cell Loss J. Immunol., February 1, 2001; 166(3): 1554 - 1561. [Abstract] [Full Text] [PDF]

				S. M. Varga, E. L. Wissinger, and T. J. Braciale The Attachment (G) Glycoprotein of Respiratory Syncytial Virus Contains a Single Immunodominant Epitope That Elicits Both Th1 and Th2 CD4+ T Cell Responses J. Immunol., December 1, 2000; 165(11): 6487 - 6495. [Abstract] [Full Text] [PDF]

				M. K. Maini, N. Gudgeon, L. R. Wedderburn, A. B. Rickinson, and P. C. L. Beverley Clonal Expansions in Acute EBV Infection Are Detectable in the CD8 and not the CD4 Subset and Persist with a Variable CD45 Phenotype J. Immunol., November 15, 2000; 165(10): 5729 - 5737. [Abstract] [Full Text] [PDF]

				S. M. Varga and R. M. Welsh High Frequency of Virus-Specific Interleukin-2-Producing CD4+ T Cells and Th1 Dominance during Lymphocytic Choriomeningitis Virus Infection J. Virol., May 1, 2000; 74(9): 4429 - 4432. [Abstract] [Full Text]

				M. K. Slifka, R. R. Pagarigan, and J. L. Whitton NK Markers Are Expressed on a High Percentage of Virus-Specific CD8+ and CD4+ T Cells J. Immunol., February 15, 2000; 164(4): 2009 - 2015. [Abstract] [Full Text] [PDF]

				M. K. Slifka and J. L. Whitton Activated and Memory CD8+ T Cells Can Be Distinguished by Their Cytokine Profiles and Phenotypic Markers J. Immunol., January 1, 2000; 164(1): 208 - 216. [Abstract] [Full Text] [PDF]

				A. Holz, A. Bot, B. Coon, T. Wolfe, M. J. Grusby, and M. G. von Herrath Disruption of the STAT4 Signaling Pathway Protects from Autoimmune Diabetes While Retaining Antiviral Immune Competence J. Immunol., November 15, 1999; 163(10): 5374 - 5382. [Abstract] [Full Text] [PDF]

				W. Rees, J. Bender, T. K. Teague, R. M. Kedl, F. Crawford, P. Marrack, and J. Kappler An inverse relationship between T cell receptor affinity and antigen dose during CD4+ T cell responses in vivo and in vitro PNAS, August 17, 1999; 96(17): 9781 - 9786. [Abstract] [Full Text] [PDF]

				C. Zimmermann and H. Pircher A Novel Approach to Visualize Polyclonal Virus-Specific CD8 T Cells In Vivo J. Immunol., May 1, 1999; 162(9): 5178 - 5182. [Abstract] [Full Text] [PDF]

				N. Arbour, D. Naniche, D. Homann, R. J. Davis, R. A. Flavell, and M. B.A. Oldstone c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Signaling Pathways Have Divergent Roles in CD8+ T Cell-mediated Antiviral Immunity J. Exp. Med., March 25, 2002; 195(7): 801 - 810. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Varga, S. M. Articles by Welsh, R. M. Search for Related Content PubMed PubMed Citation Articles by Varga, S. M. Articles by Welsh, R. M. Pubmed/NCBI databases Substance via MeSH