In the pathway, NF-κB/Rel proteins are bound and inhibited by IκB proteins. Growth factors, proinflammatory cytokines, chemotherapy, radiotherapy, and antigen receptors activate an IKK complex, which phosphorylates IκB proteins. Phosphorylation of IκB leads to its ubiquitination and proteasomal degradation, freeing NF-κB/Rel complexes. The transcription factor NF-κB is thereby released and promotes the expression of cytokines, cell adhesion molecules, and antiapoptotic proteins. The NF-κB signal transduction pathway in development and dysfunction of the immune system. In NF-κB pathway, most proteins regulate the expression of genes influencing a broad range of biological processes including innate and adaptive immunity, inflammation, stress responses, B-cell development, and lymphoid organogenesis.
Nuclear factor kappa B is a dimer belonging to Rel family, that contains a highly conserved Rel-homology domain (RHD). The NFκB proteins have five different monomers that share a Rel homology domain in their N-terminus. The p105 and p100 which precursors of NFκB1 and NFκB2 that are transformed to mature NFκB subunits (p50 and p52) by the ubiquitin pathway. The nuclear translocation of NFκB, inhibitory kappa B (IκB) proteins, and DNA binding interaction with RHD.
NFκB signalling pathway have two major ways,that as : (1) the canonical (mediated by IκB degradation), and (2) the non-canonical (p100 mediated) pathways. In the cell ,the NFκB dimers are attached to IκB proteins under normal conditions. The canonical pathway will be activated by the inflammatory reaction, for example,interleukins, TNF-α, or LPS, that leads to the activation of the IκB kinase (IKK) complex. Then NFκB becomes free, which follows it moves to the nucleus and initiates transcription of the target genes.
Full activation of naïve T cells requires at least two signals. The first signal is antigen displayed by antigen presenting cells (APCs) in the form of peptides bound to histocompatibility molecules; the recognition of antigen by T-cell receptors provides specificity to the response. The second signal, the co-stimulatory signal, is antigen nonspecific and is provided by molecules on APCs that engage particular costimulatory receptors on T cells. It stimulates T cells in conjunction with antigen. Therefore, costimulation is crucial to the development of an effective immune response of adaptive immunity. T cell costimulation is necessary for T cell proliferation, differentiation and survival. Activation of T cells without costimulation may lead to T cell anergy, T cell deletion or the development of immune tolerance.
One of the best characterized costimulatory receptors expressed by T cells is CD28, which interacts with CD80 (B7-1) and CD86 (B7-2) on the membrane of APCs. CD28 is constitutively expressed on almost all T cells, and is the major costimulatory receptor for naive T cells. The costimulatory molecules B7-1 and B7-2 are expressed mainly on APCs, including dendritic cells, macrophages, and B cells. The expression of B7-1 and B7-2 on APCs is enhanced by the presence of microbes and by cytokines that are produced in response to microbes. This regulated expression of B7 costimulators ensures that T cells respond best only when necessary — that is, when faced with pathogens. The interaction of B7-1 and B7-2 with CD28, in concert with T-cell–receptor signaling, promotes the expansion of antigen-stimulated T cells and their differentiation into effector and memory cells.
Another costimulatory receptor expressed by T cells is ICOS (Inducible Costimulator), which interacts with ICOS-L. ICOS, which is a member of the CD28 family of costimulatory molecules, was identified in 1999 as a molecule expressed primarily on activated human T cells. Induced upon activation, ICOS appears to be an ideal target for modifying T-cell-mediated immune responses. The activation and effector function of ICOS for both Th1 and Th2 cell suggests a central role for it in the generation and maintenance of humoral immunity.
Numerous costimulatory molecules have been identified playing a role in the initiation of immune responses by T and B lymphocytes. Activation of B cells requires CD40-CD40L interactions for proper antibody response: promoting survival, cytokine receptor expression, and inducing antibody class switch. Without this costimulation B cells cannot proliferate further.
Costimulation blockade has been developed as a specific field of interest towards achieving improved antigen specific control over transplant rejection while minimizing broad attenuation of protective immunity. This field has grown rapidly in the past decade and is now poised to become a valuable therapeutic option for transplant clinicians. Recent discoveries have highlighted the duality of costimulatory molecules: they can be either stimulatory (costimulation) or inhibitory (coinhibition). It has been discovered that the various aspects of immune dysfunction seen in cancer are involved with the presence of coinhibitory (ex: PD-1, PD-L1, CTLA-4, BTLA) and costimulatory (ex: CD28, ICOS, 4-1BB, CD40, OX40, CD27) signaling.