B cell response after MMTV infection: extrafollicular plasmablasts represent the main infected population and can transmit viral infection

The immune response to mouse mammary tumor virus (MMTV) relies on the presentation of an MMTV-encoded superantigen by infected B cells to superantigen-specific T cells. The initial extrafollicular B cell differentiation involved the generation of B cells expressing low levels of B220. These B220low B cells corresponded to plasmablasts that expressed high levels of CD43 and syndecan-1 and were CD62 ligand- and IgD-. Viral DNA was detected nearly exclusively in these B220low B cells by PCR, and retroviral type-A particles were observed in their cytoplasm by electron microscopy. An MMTV transmission to the offspring was also achieved after transfer of B220low CD62 ligand- CD43+ plasmablasts into noninfected females. These data suggest that B220low plasmablasts, representing the bulk of infected B cells, are capable of sustaining viral replication and may be involved in the transmission of MMTV.     

IgM production by bone marrow plasmablasts contributes to long-term protection against intracellular bacterial infection

IgM responses are well known to occur early postinfection and tend to be short-lived, which has suggested that this Ig does not significantly contribute to long-term immunity. In this study, we demonstrate that chronic infection with the intracellular bacterium Ehrlichia muris elicits a protective, long-term IgM response. Moreover, we identified a population of CD138(high)IgM(high) B cells responsible for Ag-specific IgM production in the bone marrow. The IgM-secreting cells, which exhibited characteristics of both plasmablasts and plasma cells, contributed to protection against fatal ehrlichial challenge. Mice deficient in activation-induced cytidine deaminase, which produce only IgM, were protected against fatal ehrlichial challenge infection. The IgM-secreting cells that we have identified were maintained in the bone marrow in the absence of chronic infection, as antibiotic-treated mice remained protected against challenge infection. Our studies identify a cell population that is responsible for the IgM production in the bone marrow, and they highlight a novel role for IgM in the maintenance of long-term immunity during intracellular bacterial infection.     

TNF-alpha-dependent and -independent maturation of dendritic cells and recruited CD11c(int)CD11b+ Cells during oral Salmonella infection

Maturation of dendritic cells (DC) is crucial for their ability to induce adaptive immunity. Although several mediators of DC maturation have been found, their contributions to DC maturation during infection are poorly understood. In this study we show that murine conventional (CD11c(high)) DC up-regulate costimulatory molecules in a subset-specific manner after oral Salmonella infection. Although both CD8alpha+ and CD8alpha- subsets increase CD86 expression, CD40 was preferentially up-regulated on CD8alpha+ DC, and CD80 was preferentially increased on CD8alpha- DC. In addition, high levels of CD80 and CD86 were found on CD11c(int)CD11b+ cells that accumulated in infected organs. Costimulatory molecules were simultaneously induced on CD11c(high) and CD11c(int)CD11b+ cells in Peyer's patches, mesenteric lymph nodes and spleen 5 days after infection despite different kinetics of peak bacterial burden in these organs. Up-regulation of costimulatory molecules occurred on all DC within the respective subset. Moreover, <1% of CD11c-expressing cells associated with Salmonella expressing enhanced GFP in vivo. Thus, DC maturation did not depend on bacterial uptake. Rather, infection-induced up-regulation of CD80, CD86, and CD40 on CD11c-expressing cells of mesenteric lymph nodes was dependent on TNFR type I (TNFRI) signaling. Although indirect up-regulation of costimulatory molecules on DC and CD11c(int)CD11b+ cells was TNFRI dependent, cells directly associated with Salmonella were able to mature independently of TNFRI signaling. Thus, Salmonella-induced TNF-alpha is an important mediator of indirect DC maturation during infection, whereas a TNF-alpha-independent maturation pathway contributes to direct maturation of bacteria-associated DC.     

The CD9 tetraspanin is not required for the development of peripheral B cells or for humoral immunity

The CD9 tetraspanin is known to be expressed at high levels on marginal zone (MZ) B cells, B-1 B cells, and plasma cells, and its expression is believed to be dependent on signals derived via Btk. In CD9 null mice, however, the development and survival of MZ B cells, B-1 B cells, and plasma cells all appear to be unaffected, and humoral immune responses to T-dependent and T-independent Ags are similar to those seen in wild-type littermate controls. In wild-type mice, CD9 levels may serve to distinguish between the presumed MZ precursor B cell population in the spleen and other IgD-expressing transitional B cells that express lower levels of CD21 and CD1d. These results suggest that CD9 is dispensable for B cell development and humoral immunity, but that this protein may serve as an additional marker for the presumed MZ precursor population of splenic B cells.     

IL-10-producing B220+CD11c- APC in mouse spleen

APC acting at the early stages of an immune response can shape the nature of that response. Such APC will include dendritic cells (DCs) but may also include populations of B cells such as marginal zone B cells in the spleen. In this study, we analyze APC populations in mouse spleen and compare the phenotype and function of B220(+)CD11c(-) populations with those of CD11c(+) spleen DC subsets. Low-density B220(+) cells had morphology similar to DCs and, like DCs, they could stimulate naive T cells, and expressed high levels of MHC and costimulatory molecules. However, the majority of the B220(+) cells appeared to be of B cell lineage as demonstrated by coexpression of CD19 and surface Ig, and by their absence from RAG-2(-/-) mice. The phenotype of these DC-like B cells was consistent with that of B cells in the marginal zone of the spleen. On bacterial stimulation, they preferentially produced IL-10 in contrast to the DCs, which produced IL-12. Conventional B cells did not produce IL-10. The DC-like B cells could be induced to express low levels of the DC marker CD11c with maturational stimuli. A minority of the B220(+)CD11c(-) low-density cells did not express CD19 and surface Ig and may be a DC subset; this population also produced IL-10 on bacterial stimulation. B220(+) APC in mouse spleen that stimulate naive T cells and preferentially produce IL-10 may be involved in activating regulatory immune responses.     

Marked expansion of CD11c+CD8+ T-cells in melanoma-bearing mice induced by anti-4-1BB monoclonal antibody

4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily, is expressed on activated T-cells, and 4-1BB signaling due to interaction with 4-1BB ligand or ligation with anti-4-1BB monoclonal antibody (mAb) costimulates T cells. It has been shown that administration of anti-4-1BB mAb induces anti-tumor immunity in mice, but the nature of the cellular subsets responsible for this immunity is uncertain. In this study we found that anti-4-1BB mAb administration to B16F10 melanoma-bearing mice induced marked expansion of CD11c+CD8+ T-cells in parallel with suppression of pulmonary tumors. The mAb-treated mice produced higher levels of IFN- in their tumor tissues, spleen and lymph nodes than mice exposed to control antibody. When the CD11c+CD8+ T-cells were purified and re-stimulated in vitro, they produced high levels of the Th1 cytokines, IFN- and IL-2, but low levels of the Th2 cytokines, IL-4 and IL-10. Furthermore, they expressed high levels of 4-1BB and CD107a, a marker of activated cytotoxic T-lymphocytes. Our results suggest that CD11c+CD8+ T-cells play a role in the anti-tumor immunity induced by anti-4-1BB mAb.     

Germinal center dendritic cells express more ICAM-1 than extrafollicular dendritic cells and ICAM-1/LFA-1 interactions are involved in the capacity of dendritic cells to induce PBMCs proliferation.

Germinal center dendritic cells (GCDCs) have been identified as CD11c(+) CD4(+) CD3(-) cells located in GCs with the ability of inducing marked proliferation of allogenic T cells. Using immunofluorescence techniques, we have observed that this CD11c(+) CD4(+) CD3(-) immunophenotype identified GCDCs but also a subset of extrafollicular DCs. By flow cytometry, we were able to discriminate the GCDCs (CD11c(high) CD4(high) lin(-)) from the other tonsil DCs. By immunofluorescence and flow cytometry, we found that dendritic cells of germinal centers express more intracellular adhesion molecule-1 (ICAM-1) (CD54) than extrafollicular dendritic cells. Proliferation of peripheral blood mononuclear cells (PBMCs) induced by coculture with purified CD11c(+) CD4(+) CD3(-) DCs was reduced by addition of blocking anti-CD54 antibodies. In summary, distinct levels of ICAM-1 expression allow the distinction between GCDCs and extrafollicular DCs, and cellular interactions mediated by CD54 are likely to play a role in the capacity of GCDC to stimulate allogenic PBMC proliferation.     

Antigen-driven induction of polyreactive IgM during intracellular bacterial infection

Polyreactivity is well known as a property of natural IgM produced by B-1 cells. We demonstrate that polyreactive IgM is also generated during infection of mice with Ehrlichia muris, a tick-borne intracellular bacterial pathogen. The polyreactive IgM bound self and foreign Ags, including single-stranded and double-stranded DNA, insulin, thyroglobulin, LPS, influenza virus, and Borrelia burgdorferi. Production of polyreactive IgM during infection was Ag driven, not due to polyclonal B cell activation, as the majority of polyreactive IgM recognized ehrlichial Ag(s), including an immunodominant outer membrane protein. Monoclonal polyreactive IgM derived from T cell-independent spleen plasmablasts, which was germline-encoded, also bound cytoplasmic and nuclear Ags in HEp-2 cells. Polyreactive IgM protected immunocompromised mice against lethal bacterial challenge infection. Serum from human ehrlichiosis patients also contained polyreactive and self-reactive IgM. We propose that polyreactivity increases IgM efficacy during infection but may also exacerbate or mollify the response to foreign and self Ags.     

Long-term maintenance of polysaccharide-specific antibodies by IgM-secreting cells

Many bacteria-associated polysaccharides induce long-lived Ab responses that protect against pathogenic microorganisms. The maintenance of polysaccharide-specific Ab titers may be due to long-lived plasma cells or ongoing Ag-driven B cell activation due to polysaccharide persistence. BALB/c and V(H)J558.3 transgenic mice respond to α1→3-dextran (DEX) by generating a peak anti-DEX response at 7 d, followed by maintenance of serum Ab levels for up to 150 d. Analysis of the cellular response to DEX identified a population of short-lived, cyclophosphamide-sensitive DEX-specific plasmablasts in the spleen, and a quiescent, cyclophosphamide-resistant DEX-specific Ab-secreting population in the bone marrow. BrdU pulse-chase experiments demonstrated the longevity of the DEX-specific Ab-secreting population in the bone marrow. Splenic DEX-specific plasmablasts were located in the red pulp with persisting DEX-associated CD11c(+) dendritic cells 90 d after immunization, whereas DEX was not detected in the bone marrow after 28 d. Selective depletion of short-lived DEX-specific plasmablasts and memory B1b B cells using cyclophosphamide and anti-CD20 treatment had a minimal impact on the maintenance of serum anti-DEX Abs. Collectively, these findings demonstrate that the maintenance of serum polysaccharide-specific Abs is the result of continuous Ag-driven formation of short-lived plasmablasts in the spleen and a quiescent population of Ab-secreting cells maintained in the bone marrow for a long duration.     

Aborted germinal center reactions and B cell memory by follicular T cells specific for a B cell receptor V region peptide

A fundamental problem in immunoregulation is how CD4(+) T cells react to immunogenic peptides derived from the V region of the BCR that are created by somatic mechanisms, presented in MHC II, and amplified to abundance by B cell clonal expansion during immunity. BCR neo Ags open a potentially dangerous avenue of T cell help in violation of the principle of linked Ag recognition. To analyze this issue, we developed a murine adoptive transfer model using paired donor B cells and CD4 T cells specific for a BCR-derived peptide. BCR peptide-specific T cells aborted ongoing germinal center reactions and impeded the secondary immune response. Instead, they induced the B cells to differentiate into short-lived extrafollicular plasmablasts that secreted modest quantities of Ig. These results uncover an immunoregulatory process that restricts the memory pathway to B cells that communicate with CD4 T cells via exogenous foreign Ag.     

Single and coexpression of CXCR4 and CXCR5 identifies CD4 T helper cells in distinct lymph node niches during influenza virus infection

Influenza virus infection results in strong, mainly T-dependent, extrafollicular and germinal center B cell responses, which provide lifelong humoral immunity against the homotypic virus strain. Follicular T helper cells (T(FH)) are key regulators of humoral immunity. Questions remain regarding the presence, identity, and function of T(FH) subsets regulating early extrafollicular and later germinal center B cell responses. This study demonstrates that ICOS but not CXCR5 marks T cells with B helper activity induced by influenza virus infection and identifies germinal center T cells (T(GC)) as lymph node-resident CD4(+) ICOS(+) CXCR4(+) CXCR5(+) PSGL-1(lo) PD-1(hi) cells. The CXCR4 expression intensity further distinguished their germinal center light and dark zone locations. This population emerged strongly in regional lymph nodes and with kinetics similar to those of germinal center B cells and were the only T(FH) subsets missing in influenza virus-infected, germinal center-deficient SAP(-/-) mice, mice which were shown previously to lack protective memory responses after a secondary influenza virus challenge, thus indicting the nonredundant functions of CXCR4- and CXCR5-coexpressing CD4 helper cells in antiviral B cell immunity. CXCR4-single-positive T cells, present in B cell-mediated autoimmunity and regarded as "extrafollicular" helper T cells, were rare throughout the response, despite prominent extrafollicular B cell responses, revealing fundamental differences in autoimmune- and infection-induced T-dependent B cell responses. While all ICOS(+) subsets induced similar antibody levels in vitro, CXCR5-single-positive T cells were superior in inducing B cell proliferation. The regulation of T cell localization, marked by the single and coexpression of CXCR4 and CXCR5, might be an important determinant of T(FH) function.     

Alphavirus-induced encephalomyelitis: antibody-secreting cells and viral clearance from the nervous system

Sindbis virus (SINV) infection of the central nervous system (CNS) provides a model for understanding the role of the immune response in recovery from alphavirus infection of neurons. Virus clearance occurred in three phases: clearance of infectious virus (days 3 to 7), clearance of viral RNA (days 8 to 60), and maintenance of low levels of viral RNA (>day 60). The antiviral immune response was initiated in the cervical lymph nodes with rapid extrafollicular production of plasmablasts secreting IgM, followed by germinal center production of IgG-secreting and memory B cells. The earliest inflammatory cells to enter the brain were CD8(+) T cells, followed by CD4(+) T cells and CD19(+) B cells. During the clearance of infectious virus, effector lymphocytes in the CNS were primarily CD8(+) T cells and IgM antibody-secreting cells (ASCs). During the clearance of viral RNA, there were more CD4(+) than CD8(+) T cells, and B cells included IgG and IgA ASCs. At late times after infection, ASCs in the CNS were primarily CD19(+) CD38(+) CD138(-) Blimp-1(+) plasmablasts, with few fully differentiated CD38(-) CD138(+) Blimp-1(+) plasma cells. CD19(+) CD38(+) surface Ig(+) memory B cells were also present. The level of antibody to SINV increased in the brain over time, and the proportion of SINV-specific ASCs increased from 15% of total ASCs at day 14 to 90% at 4 to 6 months, suggesting specific retention in the CNS during viral RNA persistence. B cells in the CNS continued to differentiate, as evidenced by accumulation of IgA ASCs not present in peripheral lymphoid tissue and downregulation of major histocompatibility complex (MHC) class II expression on plasmablasts. However, there was no evidence of germinal center activity or IgG avidity maturation within the CNS.     

CD1d and CD1c expression in human B cells is regulated by activation and retinoic acid receptor signaling

B cell activation and Ab production in response to protein Ags requires presentation of peptides for recruitment of T cell help. We and others have recently demonstrated that B cells can also acquire innate help by presenting lipid Ags via CD1d to NKT cells. Given the newfound contribution of NKT cells to humoral immunity, we sought to identify the pathways that regulate CD1 molecule expression in human B cells. We show that ex vivo, activated and memory B cells expressed lower levels of CD1d compared with resting, naive, and marginal zone-like B cells. In vitro, CD1d was downregulated by all forms of B cell activation, leaving a narrow temporal window in which B cells could activate NKT cells. CD1c expression and function also decreased following activation by CD40L alone, whereas activation via the BCR significantly upregulated CD1c, particularly on marginal zone-like B cells. We found that the CD40L-induced downregulation of CD1d and CD1c correlated with diminished expression of retinoic acid receptor α (RARα) response genes, an effect that was reversed by RARα agonists. However, BCR-induced upregulation of CD1c was independent of the RAR pathway. Our findings that both CD1d and CD1c are upregulated by RARα signaling in human B cells is distinct from effects reported in dendritic cells, in which CD1c is inversely downregulated. One functional consequence of CD1d upregulation by retinoic acid was NKT cell cytotoxicity toward B cells. These results are central to our understanding of how CD1-restricted T cells may control humoral immunity.     

Differential surface expression and possible function of 9-O- and 7-O-acetylated GD3 (CD60 b and c) during activation and apoptosis of human tonsillar B and T lymphocytes

The disialoganglioside GD3 (CD60 a) and its O-acetylated variants have previously been described as surface molecules of human T lymphocytes of the peripheral blood system. Here we report the expression of the 9-O-, and 7-O-acetylated disialoglycans of GD3 (CD60 b and CD60 c respectively) on human tonsillar lymphocytes. CD60 b and c are surface-expressed on activated germinal centre B cells and colocalize in raft-like structures on the cell surface together with the cytoplasmic tyrosine kinase Lyn and Syk. Addition of CD60 b and c mAb together with anti-IgM/IL-4 to in vitro cultivated tonsillar B cells resulted in a costimulatory effect. During spontaneous and staurosporine-induced apoptosis a distinct population of activated annexin V+/CD60 b+/CD60 c- B cells was observed. CD60 b and c are also found on cells of the extrafollicular T cell area. On tonsillar T cells, CD60 b mAb had a costimulatory effect together with PHA while CD60 c mAb alone was sufficient to induce proliferation. In further contrast to B cells, during apoptosis a distinct CD60 b+ T cell subpopulation was not observed. Together, surface-expressed CD60 b and c are differently expressed on tonsillar B and T cells and may be involved in the regulation of activation and apoptosis of lymphocytes in secondary lymphatic tissue.     

Mucosal and peripheral Lin- HLA-DR+ CD11c/123- CD13+ CD14- mononuclear cells are preferentially infected during acute simian immunodeficiency virus infection

Massive infection of memory CD4 T cells is a hallmark of early simian immunodeficiency virus (SIV) infection, with viral infection peaking at day 10 postinfection (p.i.), when a majority of memory CD4 T cells in mucosal and peripheral tissues are infected. It is not clear if mononuclear cells from the monocyte and macrophage lineages are similarly infected during this early phase of explosive HIV and SIV infections. Here we show that, at day 10 p.i., Lin(-) HLA-DR(+) CD11c/123(-) CD13(+) CD14(-) macrophages in the jejunal mucosa were infected, albeit at lower levels than CD4 memory T cells. Interestingly, Lin(-) HLA-DR(+) CD11c/123(-) CD13(+) CD14(-) macrophages in peripheral blood, like their mucosal counterparts, were preferentially infected compared to Lin(-) HLA-DR(+) CD11c/123(-) CD13(+) CD14(+) monocytes, suggesting that differentiated macrophages were selectively infected by SIV. CD13(+) CD14(-) macrophages expressed low levels of CD4 compared to CD4 T cells but expressed similar levels of CCR5 as lymphocytes. Interestingly, CD13(+) CD14(-) macrophages expressed Apobec3G at lower levels than CD13(+) CD14(+) monocytes, suggesting that intracellular restriction may contribute to the differential infection of mononuclear subsets. Taken together, our results suggest that CD13(+) CD14(-) macrophages in mucosal and peripheral tissues are preferentially infected very early during the course of SIV infection.     

Overproduction of TNF-alpha by CD8+ type 1 cells and down-regulation of IFN-gamma production by CD4+ Th1 cells contribute to toxic shock-like syndrome in an animal model of fatal monocytotropic ehrlichiosis

Human monocytotropic ehrlichiosis (HME) is an emerging, life-threatening, infectious disease caused by Ehrlichia chaffeensis, an obligate intracellular bacterium that lacks cell wall LPS. We have previously developed an animal model of severe HME using a strain of Ehrlichia isolated from Ixodes ovatus ticks (IOE). To understand the basis of susceptibility to severe monocytotropic ehrlichiosis, we compared low and high doses of the highly virulent IOE strain and the less virulent Ehrlichia muris strain that are closely related to E. chaffeensis in C57BL/6 mice. Lethal infections caused by high or low doses of IOE were accompanied by extensive liver damage, extremely elevated levels of TNF-alpha in the serum, high frequency of Ehrlichia-specific, TNF-alpha-producing CD8(+) T cells in the spleen, decreased Ehrlicha-specific CD4(+) T cell proliferation, low IL-12 levels in the spleen, and a 40-fold decrease in the number of IFN-gamma-producing CD4(+) Th1 cells. All groups contained negligible numbers of IL-4-producing cells in the spleen. Transfer of Ehrlichia-specific polyclonal Abs and IFN-gamma-producing Ehrlichia-specific CD4(+) and CD8(+) type 1 cells protected naive mice against lethal IOE challenge. Interestingly, infection with high dose E. muris provided protection against rechallenge with a lethal dose of IOE. Cross-protection was associated with substantial expansion of IFN-gamma-producing CD4(+) and CD8(+) cells, but not TNF-alpha-producing CD8(+) T cells, a high titer of IgG2a, and a low serum level of TNF-alpha. In conclusion, uncontrolled TNF-alpha production by CD8(+) T cells together with a weak CD4(+) Th1 cell response are associated with immunopathology and failure to clear IOE in the fatal model of HME.     

Polyethylene glycol-modified GM-CSF expands CD11b(high)CD11c(high) but notCD11b(low)CD11c(high) murine dendritic cells in vivo: a comparative analysis with Flt3 ligand

Dendritic cells (DC) are potent APCs that can be characterized in the murine spleen as CD11b(high)CD11c(high) or CD11b(low)CD11c(high). Daily injection of mice of Flt3 ligand (FL) into mice transiently expands both subsets of DC in vivo, but the effect of administration of GM-CSF on the expansion of DC in vivo is not well defined. To gain further insight into the role of GM-CSF in DC development and function in vivo, we treated mice with polyethylene glycol-modified GM-CSF (pGM-CSF) which has an increased half-life in vivo. Administration of pGM-CSF to mice for 5 days led to a 5- to 10-fold expansion of CD11b(high)CD11c(high) but not CD11b(low)CD11c(high) DC. DC from pGM-CSF-treated mice captured and processed Ag more efficiently than DC from FL-treated mice. Although both FL- and pGM-CSF-generated CD11b(high)CD11c(high) DC were CD8alpha-, a greater proportion of these DC from pGM-CSF-treated mice were 33D1+ than from FL-treated mice. CD11b(low)CD11c(high) DC from FL-treated mice expressed high levels of intracellular MHC class II. DC from both pGM-CSF- and FL-treated mice expressed high levels of surface class II, low levels of the costimulatory molecules CD40, CD80, and CD86 and were equally efficient at stimulating allogeneic and Ag-specific T cell proliferation in vitro. The data demonstrate that treatment with pGM-CSF in vivo preferentially expands CD11b(high)CD11c(high) DC that share phenotypic and functional characteristics with FL-generated CD11b(high)CD11c(high) DC but can be distinguished from FL-generated DC on the basis of Ag capture and surface expression of 33D1.     

Plasmodium chabaudi chabaudi infection in mice induces strong B cell responses and striking but temporary changes in splenic cell distribution

B cells and Abs play a key role in controlling the erythrocytic stage of malaria. However, little is known about the way the humoral response develops during infection. We show that Plasmodium chabaudi chabaudi causes major, but temporary changes in the distribution of leukocytes in the spleen. Despite these changes, an ordered response to infection develops, which includes vigorous extrafollicular growth of plasmablasts and germinal center formation. Early in the response, the lymphocytes in the T zone and follicles become widely spaced, and the edges of these compartments blur. This effect is maximal around the peak of parasitemia. Germinal centers are apparent by day 8, peak at day 20, and persist through day 60. Extrafollicular foci of plasmablasts are visible from day 4 and initiate a very strong plasma cell response. Initially, the plasma cells have a conventional red pulp distribution, but by day 10 they are unconventionally sited in the periarteriolar region of the white pulp. In this region they form clusters occupying part of the area normally filled by T cells. B cells are absent from the marginal zone for at least 30 days after the peak of infection, although flow cytometry shows their continued presence in the spleen throughout infection. Relatively normal splenic architecture is regained by day 60 of infection. These results show that the changes in splenic cell distribution are linked to the presence of parasites and do not seem to interfere with the development of the humoral response.     

CD11c controls herpes simplex virus 1 responses to limit virus replication during primary infection

CD11c is expressed on the surface of dendritic cells (DCs) and is one of the main markers for identification of DCs. DCs are the effectors of central innate immune responses, but they also affect acquired immune responses to infection. However, how DCs influence the efficacy of adaptive immunity is poorly understood. Here, we show that CD11c(+) DCs negatively orchestrate both adaptive and innate immunity against herpes simplex virus type 1 (HSV-1) ocular infection. The effectiveness and quantity of virus-specific CD8(+) T cell responses are increased in CD11c-deficient animals. In addition, the levels of CD83, CD11b, alpha interferon (IFN-α), and IFN-β, but not IFN-γ, were significantly increased in CD11c-deficient animals. Higher levels of IFN-α, IFN-β, and CD8(+) T cells in the CD11c-deficient mice may have contributed to lower virus replication in the eye and trigeminal ganglia (TG) during the early period of infection than in wild-type mice. However, the absence of CD11c did not influence survival, severity of eye disease, or latency. Our studies provide for the first time evidence that CD11c expression may abrogate the ability to reduce primary virus replication in the eye and TG via higher activities of type 1 interferon and CD8(+) T cell responses.