LCMV-specific CD4 T cell dependent polyclonal B-cell activation upon persistent viral infection is short lived and extrafollicular.

Persistent virus infections with non- or poorly cytopathic viruses are commonly associated with B cell dysregulations. These include the induction of hypergammaglobulinemia and the emergence of virus-unspecific antibodies. These seemingly unspecific antibody responses interfere with the virus-specific humoral immunity and contribute to delayed virus control.

Sustained T follicular helper cell response is essential for control of chronic viral infection.

During chronic viral infections, both CD8 and CD4 T cell responses are functionally compromised. Alongside exhaustion of CD8 T cells during chronic viral infections, it has also been documented that the CD4 T cells have an increased propensity to differentiate toward CXCR5 T follicular helper cell (T) lineage. Whether these T cells contribute to the immune response to chronic viral infection has remained unclear.

On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection.

Chronic viral infections are often characterized by CD8 T-cell responses with poor cytokine secretion potential and limited expansion of the CD8 T-cell pool, collectively referred to as CD8 T-cell exhaustion. Exhaustion of lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells was shown to be partially regulated by the inhibitory receptor programmed death 1 (PD-1). Here, we demonstrate that exhausted LCMV-specific CD8 T cells also express the negative regulatory receptor lymphocyte activation gene 3 (LAG-3) which is mainly expressed on cells co-expressing the negative regulatory receptors PD-1 and Tim-3.

Kinetic and mechanistic requirements for helping CD8 T cells.

The requirements for the generation of fully competent long-lived memory CD8 T cells and in particular the role and the mechanisms of help from CD4 T cells remain ill-defined. Memory CD8 T cells generated in the absence of CD4 T cell help often have an impaired recall proliferation and are thus unable to confer protection against certain pathogens. However, the timing and the mechanisms involved in the delivery of help are still unclear and differ between various experimental systems.

Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection.

In persistent viral infections, the host's immune system is challenged by the constant exposure to antigen, potentially causing continuous activation of CD8(+) T cells with subsequent immunopathology. Here we demonstrate, for experimental chronic lymphocytic choriomeningitis virus and human HIV infection, that upon prolonged in vivo exposure to antigen, TCR-triggered Ca(2+) flux, degranulation, and cytotoxicity are maintained on a cellular level, whereas cytokine production is severely impaired because of a selective defect in activation-induced NFAT nuclear translocation. During chronic infection, this differential regulation of pathways leading to diverse effector functions may allow CD8(+) T cells to sustain some degree of local viral control by direct cytotoxicity while limiting systemic immune pathology by silencing cytokine production.

Long-lived memory CD8+ T cells are programmed by prolonged antigen exposure and low levels of cellular activation.

CD8+ T cells play a crucial role in controlling intracellular pathogens. The level of memory CD8+ T cells developing after vaccination or infection influences the degree of T cell-mediated protection after secondary infection. We used defined animal models and infections/immunizations by replicating or non-replicating antigens to define on a molecular and cellular level in vivo the parameters that identify and shape long-lived CD8+ T cell memory.