Lisa Togher

Resolution of a chronic viral infection after interleukin-10 receptor blockade

A defining characteristic of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses cellular immune responses by modulating the function of T cells and antigen-presenting cells. In this paper, we report that IL-10 production is drastically increased in mice persistently infected with lymphocytic choriomeningitis virus. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid resolution of the persistent infection. IL-10 secretion was diminished and interferon γ production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8α+ dendritic cell (DC) numbers declined early after infection, whereas CD8α− DC numbers were not affected. CD8α− DCs supported IL-10 production and subsequent dampening of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10–mediated immune suppression, preventing IL-10 priming by CD8α− DCs and enhancing antiviral responses and thereby resolving infection without causing immunopathology.

T-bet controls autoaggressive CD8 lymphocyte responses in type 1 diabetes

The T-box transcription factor T-bet is known to control lineage commitment and interferon-γ production by T helper 1 (Th1) CD4 lymphocytes. We report here that T-bet is essential for development of CD8 lymphocyte-dependent autoimmune diabetes (type 1 diabetes [T1D]) in the rat insulin promoter–lymphocytic choriomeningitis virus (LCMV) transgenic model for virally induced T1D. In the absence of T-bet, autoaggressive (anti-LCMV) CD8 lymphocytes were reduced in number and produced less IFN-γ, but increased IL-2 compared with controls. Further analysis showed that T-bet intrinsically controls the generation, but not apoptosis, maintenance, or secondary expansion of antiviral effector/memory CD8 lymphocytes. This observation points toward a therapeutic opportunity for the treatment of T1D and other autoimmune disorders.

Transforming Growth Factor-β Suppresses the Activation of CD8+ T-Cells When Naïve but Promotes Their Survival and Function Once Antigen Experienced : A Two-Faced Impact on Autoimmunity

OBJECTIVE—Transforming growth factor-β (TGF-β) can exhibit strong immune suppression but has also been shown to promote T-cell growth. We investigated the differential effect of this cytokine on CD8+ T-cells in autoimmunity and antiviral immunity. RESEARCH DESIGN AND METHODS—We used mouse models for virally induced type 1 diabetes in conjunction with transgenic systems enabling manipulation of TGF-β expression or signaling in vivo. RESULTS—Surprisingly, when expressed selectively in the pancreas, TGF-β reduced apoptosis of differentiated autoreactive CD8+ T-cells, favoring their expansion and infiltration of the islets. These results pointed to drastically opposite roles of TGF-β on naïve compared with antigen-experienced/memory CD8+ T-cells. Indeed, in the absence of functional TGF-β signaling in T-cells, fast-onset type 1 diabetes caused by activation of naïve CD8+ T-cells occurred faster, whereas slow-onset disease depending on accumulation and activation of antigen-experienced/memory CD8+ T-cells was decreased. TGF-β receptor–deficient CD8+ T-cells showed enhanced activation and expansion after lymphocytic choriomeningitis virus infection in vivo but were more prone to apoptosis once antigen experienced and failed to survive as functional memory cells. In vitro, TGF-β suppressed naïve CD8+ T-cell activation and γ-interferon production, whereas memory CD8+ T-cells stimulated in the presence of TGF-β showed enhanced survival and increased production of interleukin-17 in conjunction with γ-interferon. CONCLUSIONS—The effect of TGF-β on CD8+ T-cells is dependent on their differentiation status and activation history. These results highlight a novel aspect of the pleiotropic nature of TGF-β and have implications for the design of immune therapies involving this cytokine.

TGF-β suppresses the activation of CD8+ T cells when naïve but promotes their survival and function once antigen-experienced: a two-faced impact on autoimmunity

OBJECTIVE—Transforming growth factor-β (TGF-β) can exhibit strong immune suppression but has also been shown to promote T-cell growth. We investigated the differential effect of this cytokine on CD8+ T-cells in autoimmunity and antiviral immunity. RESEARCH DESIGN AND METHODS—We used mouse models for virally induced type 1 diabetes in conjunction with transgenic systems enabling manipulation of TGF-β expression or signaling in vivo. RESULTS—Surprisingly, when expressed selectively in the pancreas, TGF-β reduced apoptosis of differentiated autoreactive CD8+ T-cells, favoring their expansion and infiltration of the islets. These results pointed to drastically opposite roles of TGF-β on naïve compared with antigen-experienced/memory CD8+ T-cells. Indeed, in the absence of functional TGF-β signaling in T-cells, fast-onset type 1 diabetes caused by activation of naïve CD8+ T-cells occurred faster, whereas slow-onset disease depending on accumulation and activation of antigen-experienced/memory CD8+ T-cells was decreased. TGF-β receptor–deficient CD8+ T-cells showed enhanced activation and expansion after lymphocytic choriomeningitis virus infection in vivo but were more prone to apoptosis once antigen experienced and failed to survive as functional memory cells. In vitro, TGF-β suppressed naïve CD8+ T-cell activation and γ-interferon production, whereas memory CD8+ T-cells stimulated in the presence of TGF-β showed enhanced survival and increased production of interleukin-17 in conjunction with γ-interferon. CONCLUSIONS—The effect of TGF-β on CD8+ T-cells is dependent on their differentiation status and activation history. These results highlight a novel aspect of the pleiotropic nature of TGF-β and have implications for the design of immune therapies involving this cytokine.

Increased Memory Conversion of Naïve CD8 T Cells Activated during Late Phases of Acute Virus Infection Due to Decreased Cumulative Antigen Exposure

Background Memory CD8 T cells form an essential part of protective immunity against viral infections. Antigenic load, costimulation, CD4-help, cytokines and chemokines fluctuate during the course of an antiviral immune response thus affecting CD8 T cell activation and memory conversion. Methodology/Principal Findings In the present study, naïve TCR transgenic LCMV-specific P14 CD8 T cells engaged at a late stage during the acute antiviral LCMV response showed reduced expansion kinetics but greater memory conversion in the spleen. Such late activated cells displayed a memory precursor effector phenotype already at the peak of the systemic antiviral response, suggesting that the environment determined their fate during antigen encounter. In the spleen, the majority of late transferred cells exhibited a central memory phenotype compared to the effector memory displayed by the early transferred cells. Increasing the inflammatory response by exogenous administration of IFNγ, PolyI:C or CpG did not affect memory conversion in the late transferred group, suggesting that the diverging antigen load early versus later during acute infection had determined their fate. In agreement, reduction in the LCMV antigenic load after ribavirin treatment enhanced the contribution of early transferred cells to the long lasting memory pool. Conclusions/Significance Our results show that naïve CD8 cells, exposed to reduced duration or concentration of antigen during viral infection convert into memory more efficiently, an observation that could have significant implications for vaccine design.

Minimal Impact of a De Novo–Expressed β-Cell Autoantigen on Spontaneous Diabetes Development in NOD Mice

During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such “antigenic spreading” can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic β-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo–expressed β-cell autoantigens will not accelerate autoimmunity unless large numbers of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present.