Human CD4+ T Cells Displaying Viral Epitopes Elicit a Functional Virus-Specific Memory CD8+ T Cell Response

Background: Myelin-specific T cells are implicated in multiple sclerosis (MS) and drive experimental autoimmune encephalomyelitis (EAE). EAE is commonly induced with short peptides, whereas in MS, whole myelin proteins are available for immune response. We asked whether immunization with the immunoglobulin-like domain of myelin oligodendrocyte glycoprotein (MOGIgd, residues 1–125) might induce distinct CD4+ T-cell response and/or a stronger CD8+ T-cell response, compared to the 21 amino acid immunodominant MHC II-associating peptide (p35–55). Objectives: Compare both EAE and T-cell responses in C57BL/6 mice immunized with MOGIgd and MOG p35–55. Methods: Cytokine production, and chemokine receptor expression by CD4+ and CD8+ T cells in the mouse central nervous system (CNS), were analyzed by flow cytometry. Results: MOGIgd triggered progression to more severe EAE than MOG p35–55, despite similar time of onset and overall incidence. EAE in MOGIgd-immunized mice was characterized by an increased percentage of CXCR3+ interferon-γ-producing CD4+ T cells in CNS. The CD8+ T-cell response to both immunogens was similar. Conclusions: Increased incidence of severe disease following MOGIgd immunization, accompanied by an increased percentage of CD4+ T cells in the CNS expressing CXCR3 and producing interferon-γ, identifies a pathogenic role for interferon-γ that is not seen when disease is induced with a single Major Histocompatibility Complex (MHC) II-associating epitope.

Download Full-text

Regulatory CD4+CD25+ T Cells Restrict Memory CD8+ T Cell Responses

Journal of Experimental Medicine ◽

10.1084/jem.20011347 ◽

2002 ◽

Vol 196 (12) ◽

pp. 1585-1592 ◽

Cited By ~ 157

Author(s):

Mischo Kursar ◽

Kerstin Bonhagen ◽

Joachim Fensterle ◽

Anne Köhler ◽

Robert Hurwitz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Secondary Infection ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Cell Responses ◽

Boost Immunization ◽

Memory Cd8 T Cell

CD4+ T cell help is important for the generation of CD8+ T cell responses. We used depleting anti-CD4 mAb to analyze the role of CD4+ T cells for memory CD8+ T cell responses after secondary infection of mice with the intracellular bacterium Listeria monocytogenes, or after boost immunization by specific peptide or DNA vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8+ T cell responses markedly enlarged the population size of antigen-specific CD8+ T cells. After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8+ T cell populations were enlarged at least 10-fold. In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells. In depletion and transfer experiments, the suppressive function could be ascribed to CD4+CD25+ T cells. Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions. Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response. Down-modulation of CD8+ T cell responses during infection could prevent harmful consequences after eradication of the pathogen.

Download Full-text

Cutting Edge: Lipopolysaccharide Induces IL-10-Producing Regulatory CD4+ T Cells That Suppress the CD8+ T Cell Response

The Journal of Immunology ◽

10.4049/jimmunol.178.9.5429 ◽

2007 ◽

Vol 178 (9) ◽

pp. 5429-5433 ◽

Cited By ~ 50

Author(s):

Joke M. M. den Haan ◽

Georg Kraal ◽

Michael J. Bevan

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

T Cell Response ◽

Cutting Edge

Download Full-text

Primary immune responses to human CMV: a critical role for IFN-γ–producing CD4+ T cells in protection against CMV disease

Blood ◽

10.1182/blood-2002-08-2502 ◽

2003 ◽

Vol 101 (7) ◽

pp. 2686-2692 ◽

Cited By ~ 299

Author(s):

Laila E. Gamadia ◽

Ester B. M. Remmerswaal ◽

Jan F. Weel ◽

Frederieke Bemelman ◽

René A. W. van Lier ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Cd4 T Cells ◽

Critical Role ◽

Cd8 T Cell ◽

T Cell Response ◽

Antibody Responses ◽

Cd4 T Cell ◽

Effector Memory

The correlates of protective immunity to disease-inducing viruses in humans remain to be elucidated. We determined the kinetics and characteristics of cytomegalovirus (CMV)–specific CD4+ and CD8+ T cells in the course of primary CMV infection in asymptomatic and symptomatic recipients of renal transplants. Specific CD8+ cytotoxic T lymphocyte (CTL) and antibody responses developed regardless of clinical signs. CD45RA−CD27+CCR7− CTLs, although classified as immature effector cells in HIV infection, were the predominant CD8 effector population in the acute phase of protective immune reactions to CMV and were functionally competent. Whereas in asymptomatic individuals the CMV-specific CD4+ T-cell response preceded CMV-specific CD8+T-cell responses, in symptomatic individuals the CMV-specific effector-memory CD4+ T-cell response was delayed and only detectable after antiviral therapy. The appearance of disease symptoms in these patients suggests that functional CD8+ T-cell and antibody responses are insufficient to control viral replication and that formation of effector-memory CD4+ T cells is necessary for recovery of infection.

Download Full-text

CD4 T cells inhibit the CD8 T cell response during low-dose virus infection

International Immunology ◽

10.1093/intimm/dxl061 ◽

2006 ◽

Vol 18 (8) ◽

pp. 1285-1293 ◽

Cited By ~ 4

Author(s):

S. Cose

Keyword(s):

T Cells ◽

T Cell ◽

Virus Infection ◽

Cell Response ◽

Cd4 T Cells ◽

Low Dose ◽

Cd8 T Cell ◽

T Cell Response

Download Full-text

Cross-Reactive Memory CD4+T Cells Alter the CD8+T-Cell Response to Heterologous Secondary Dengue Virus Infections in Mice in a Sequence-Specific Manner

Viral Immunology ◽

10.1089/vim.2008.0089 ◽

2009 ◽

Vol 22 (3) ◽

pp. 215-219 ◽

Cited By ~ 13

Author(s):

Coreen M. Beaumier ◽

Alan L. Rothman

Keyword(s):

T Cells ◽

T Cell ◽

Dengue Virus ◽

Cell Response ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

T Cell Response ◽

Virus Infections ◽

Specific Manner ◽

Memory Cd4 T Cells

Download Full-text

Promotion of a Subdominant CD8 T Cell Response during Murine Gammaherpesvirus 68 Infection in the Absence of CD4 T Cell Help

Journal of Virology ◽

10.1128/jvi.00690-14 ◽

2014 ◽

Vol 88 (14) ◽

pp. 7862-7869 ◽

Cited By ~ 2

Author(s):

Michael L. Freeman ◽

Alan D. Roberts ◽

Claire E. Burkum ◽

David L. Woodland ◽

Marcia A. Blackman

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

T Cell Response ◽

Cd4 T Cell ◽

Cell Responses ◽

Cd4 T Cell Help ◽

T Cell Help

ABSTRACTCD8 and CD4 T cells are each critically important for immune control of murine gammaherpesvirus 68 (γHV68) infection. In immunocompetent mice, acute γHV68 infection results in lifelong latency, but in the absence of CD4 T cell help, mice succumb to viral recrudescence and disease. However, the requirements for CD4 T cell help in the generation and maintenance of antiviral CD8 T cell responses are incompletely understood, and it is unclear whether there are epitope-specific differences in the requirement of CD8 T cells for CD4 help. In this report, we characterized the CD8 T cell response to γHV68 in major histocompatibility complex (MHC) class II−/−mice, which lack CD4 T cells, or after antibody-mediated depletion of CD4 T cells. All antiviral CD8 T cells exhibited marked upregulation of surface expression of the inhibitory receptor programmed death-1 (PD-1), but surprisingly, while the immunodominant memory response appeared to be functionally impaired, helpless CD8 T cells of a subdominant specificity had increased numbers and enhanced functionality. Thus, we demonstrate differential requirements for CD4 help in the antiviral CD8 T cell response to a latent gammaherpesvirus.IMPORTANCEγHV68 is a mouse pathogen closely related to the oncogenic human γHVs, which infect a majority of the world's population. Reactivation of these viruses from latency can lead to complications, disease, and even death. CD4 T cells are required for complete immune control of long-term infection, in part by providing key signals to dendritic cells that in turn instruct optimal antiviral CD8 T cell responses. We have investigated multiple virus-specific CD8 T cell responses during infection and identified a subdominant CD8 T cell response that is numerically and functionally enhanced in the absence of CD4 T cell help. This occurs in spite of high surface expression of an inhibitory receptor and in contrast to the immunodominant response, which is impaired. Our data suggest that signals from CD4 T cells are important in maintaining the CD8 T cell hierarchy during γHV infections.

Download Full-text

CD4+ T helper cells use CD154–CD40 interactions to counteract T reg cell–mediated suppression of CD8+ T cell responses to influenza

Journal of Experimental Medicine ◽

10.1084/jem.20130097 ◽

2013 ◽

Vol 210 (8) ◽

pp. 1591-1601 ◽

Cited By ~ 28

Author(s):

André Ballesteros-Tato ◽

Beatriz León ◽

Frances E. Lund ◽

Troy D. Randall

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

T Helper Cells ◽

Cd4 T Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

T Helper ◽

Cell Responses

CD4+ T cells promote CD8+ T cell priming by licensing dendritic cells (DCs) via CD40–CD154 interactions. However, the initial requirement for CD40 signaling may be replaced by the direct activation of DCs by pathogen-derived signals. Nevertheless, CD40–CD154 interactions are often required for optimal CD8+ T cell responses to pathogens for unknown reasons. Here we show that CD40 signaling is required to prevent the premature contraction of the influenza-specific CD8+ T cell response. CD40 is required on DCs but not on B cells or T cells, whereas CD154 is required on CD4+ T cells but not CD8+ T cells, NKT cells, or DCs. Paradoxically, even though CD154-expressing CD4+ T cells are required for robust CD8+ T cell responses, primary CD8+ T cell responses are apparently normal in the absence of CD4+ T cells. We resolved this paradox by showing that the interaction of CD40-bearing DCs with CD154-expressing CD4+ T cells precludes regulatory T cell (T reg cell)–mediated suppression and prevents premature contraction of the influenza-specific CD8+ T cell response. Thus, CD4+ T helper cells are not required for robust CD8+ T cell responses to influenza when T reg cells are absent.

Download Full-text