CD28 and IL-4: two heavyweights controlling the balance between immunity and inflammation

Abstract

The costimulatory receptor CD28 and IL-4Rα-containing cytokine receptors play key roles in controlling the size and quality of pathogen-specific immune responses. Thus, CD28-mediated costimulation is needed for effective primary T-cell expansion and for the generation and activation of regulatory T-cells (Treg cells), which protect from immunopathology. Similarly, IL-4Rα signals are required for alternative activation of macrophages, which counteract inflammation by type 1 responses. Furthermore, immune modulation by CD28 and IL-4 is interconnected through the promotion of IL-4 producing T-helper 2 cells by CD28 signals. Using conditionally IL-4Rα and CD28 deleting mice, as well as monoclonal antibodies, which block or stimulate CD28, or mAb that deplete Treg cells, we have studied the roles of CD28 and IL-4Rα in experimental mouse models of virus (influenza), intracellular bacteria (L. monocytogenes, M. tuberculosis), and parasite infections (T. congolense, L. major). We observed that in some, but not all settings, Treg cells and type 2 immune deviation, including activation of alternative macrophages can be manipulated to protect the host either from infection or from immunopathology with an overall beneficial outcome. Furthermore, we provide direct evidence that secondary CD8 T-cell responses to i.c. bacteria are dependent on CD28-mediated costimulation.

IL1B, IL4R, IL12RB1 and TNF gene polymorphisms are associated with Plasmodium vivax malaria in Brazil

“…IL-4R is the principal receptor of these interleukins, and when it is blocked IL-4 and IL-13 function is aborted preventing Th2 immune response modulation [40]. Only a few works investigated IL-4R variants influence on malaria infections.…”

Comparison of pro-inflammatory cytokine expression and cellular signal transduction in human macrophages infected with different influenza A viruses

“…Pathogens induce pro-inflammatory responses upon infection that may be needed for immunological disease control but also contribute to disease course [9][10][11][12][13][14][15]. Uncomplicated influenza A virus disease is caused by virus replication and self-limiting.…”

Reversing T cell immunosenescence: why, who, and how

“…Potential beneficial impacts of the 3Rs of Rejuvenation are also represented AGE (2013) 35:609-620a progressive increase in the proportion of CD28 − T cells is observed and particularly within the CD8 + T cell subset (Lang et al 2010a). CD28-mediated costimulation is needed for effective primary T cell expansion and for the generation and activation of regulatory T cells (Hünig et al 2010). CD28 signal transduction results in IL-2 gene transcription, expression of IL-2 receptor, and the stabilization of a variety of cytokines messenger RNAs.…”