Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-T cells.

Sustained T cell receptor (TCR) stimulation is required for maintaining germinal center T follicular helper (GC-T) cells. Paradoxically, TCR activation induces interleukin-2 receptor (IL-2R) expression and IL-2 production, thereby initiating a feedback loop of IL-2 signaling that normally inhibits T cells. It is unclear how GC-T cells can receive prolonged TCR signaling without succumbing to the detrimental effects of IL-2.

Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection.

Interleukin 2 (IL-2) promotes Foxp3 regulatory T (T) cell responses, but inhibits T follicular helper (T) cell development. However, it is not clear how IL-2 affects T follicular regulatory (T) cells, a cell type with properties of both T and T cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented T cell development by a Blimp-1-dependent mechanism.

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).

Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies.

Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection.

Unlabelled: Immune escape driven by selection pressure from virus-specific CD8 T cells has been demonstrated in both chimpanzees and humans infected with the hepatitis C virus (HCV). Although escape mutations have also been characterized in major histocompatibility complex (MHC) class II-restricted HCV epitopes, it is unknown whether selection-driven immune escape by CD4 T cell epitopes is a significant factor in the failure of these responses or contributes to persistent infection. To address this issue, evolution of MHC class I- and class II-restricted HCV epitopes was compared in four chimpanzees persistently infected with the virus for more than 10 years.

Variable patterns of programmed death-1 expression on fully functional memory T cells after spontaneous resolution of hepatitis C virus infection.

The inhibitory receptor programmed death-1 (PD-1) is present on CD8(+) T cells in chronic hepatitis C virus (HCV), but expression patterns in spontaneously resolving infections are incompletely characterized. Here we report that PD-1 was usually absent on memory CD8(+) T cells from chimpanzees with resolved infections, but sustained low-level expression was sometimes observed in the absence of apparent virus replication. PD-1-positive memory T cells expanded and displayed antiviral activity upon reinfection with HCV, indicating conserved function.

Ultrafast photoinduced charge separation resulting from self-assembly of a green perylene-based dye into pi-stacked arrays.

Condensation of 3,4,5-tris(n-dodecyloxy)aniline with the green chromophore 1,7-bis(N-pyrrolidinyl)perylene-3,4;9,10-tetracarboxylic dianhydride yields N,N'-bis(3,4,5-tris(n-dodecyloxy)phenyl)-1,7-bis(N-pyrrolidinyl)perylene-3,4;9,10-bis(dicarboximide), 5PDI-TAP, which absorbs light strongly from 550 to 750 nm. 5PDI-TAP dissolves readily in methylcyclohexane (MCH), resulting in self-assembly into H-aggregates. Small-angle X-ray scattering data obtained on 10(-4) M solutions of 5PDI-TAP in MCH show that the aggregates are pi-stacked monodisperse pentamers.

Rapid recruitment of virus-specific CD8 T cells restructures immunodominance during protective secondary responses.

In this study we investigate the attributes of virus-specific memory CD8 T cells which most effectively control secondary infections. By rechallenging mice that had cleared primary lymphocytic choriomeningitis virus infections, we revealed that the secondary response is remarkably swift. Within 6 h following secondary infection, the production of gamma interferon becomes detectable directly ex vivo.

Cutting edge: emergence of CD127high functionally competent memory T cells is compromised by high viral loads and inadequate T cell help.

In this report we have inspected whether difficulties in controlling viral infections negatively impacts the generation of CD127(high) memory T cells. Using both MHC class I and II tetramers we reveal that CD127(low) T cells are not necessarily rapidly deleted but can persist in a pseudoeffector state in which they display the hallmarks of activated effector cells but are functionally inferior. CD127(high) cells can, however, emerge if the infection is contained.

Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections.

The acute phase of many viral infections is associated with the induction of a pronounced CD8 T cell response which plays a principle role in clearing the infection. By contrast, certain infections are not as readily controlled. In this study, we have used the well-defined system of lymphocytic choriomeningitis virus (LCMV) infection of mice to determine quantitative and qualitative changes in virus-specific CD8 T cell responses that rapidly resolve acute infections, more slowly control protracted infections, or fail to clear chronic infections.

CD4 T cell-dependent CD8 T cell maturation.

We have investigated the contribution of CD4 T cells to the optimal priming of functionally robust memory CD8 T cell subsets. Intranasal infection of CD4 T cell-deficient (CD4(-/-)) mice with lymphocytic choriomeningitis virus resulted in the elaboration of virus-specific CD8 T cell responses that cleared the infection. However, by comparison with normal mice, the virus-specific CD8 T cells in CD4(-/-) mice were quantitatively and qualitatively different.

Restricted clonal expression of IL-2 by naive T cells reflects differential dynamic interactions with dendritic cells.

Limited frequencies of T cells express IL-2 in primary antigenic responses, despite activation marker expression and proliferation by most clonal members. To define the basis for restricted IL-2 expression, a videomicroscopic system and IL-2 reporter transgenic model were used to characterize dendritic cell (DC)-T cell interactions. T cells destined to produce IL-2 required prolonged interactions with DCs, whereas most T cells established only transient interactions with DCs and were activated, but did not express IL-2.

Ablation of CD8 and CD4 T cell responses by high viral loads.

To evaluate the impact of sustained viral loads on anti-viral T cell responses we compared responses that cleared acute lymphocytic choriomeningitis virus infection with those that were elicited but could not resolve chronic infection. During acute infection, as replicating virus was cleared, CD8 T cell responses were down-regulated, and a pool of resting memory cells developed. In chronically infected hosts, the failure to control the infection was associated with pronounced and prolonged activation of virus-specific CD8 T cells.

T cell responses to viral infections: lessons from lymphocytic choriomeningitis virus.

The elaboration of a successful immune response is critical for the clearance of viral infections. CD8 T cells can directly kill virus-infected cells and also produce cytokines that modulate virus replication. Thus, the failure to induce or sustain these responses can profoundly impact the outcome of infections.