Regulation of IL-2 Expression in Activated and Anergic T Lymphocytes

Pathway

Pathway Description

Interleukin-2 (IL-2) is a cytokine that stimulates the growth, proliferation and subsequent differentiation of immune cells such as T cells, B cells, NK cells, monocytes and macrophages. It is a powerful immunoregulatory lymphokine that was originally described as a 'T cell growth factor' and is secreted primarily by antigen-activated T cells. Human IL-2 is a 133 amino acid polypeptide with a molecular mass of 15-18 kDa. In an autocrine fashion, the antigen primed Th cell secretes IL-2, stimulating itself as well as other neighboring antigen-primed T cells to proliferate.In normal T cells, engagement of TCR-CD3 complexes, costimulation by CD28 and recruitment of LAT leads to a membrane proximal cascade of tyrosine phosphorylation events that ultimately activates multiple pathways including ERK, JNK, NF-κB and NFAT, leading to IL-2 gene expression. Deregulation of T cell function results in dire consequences for the organism such as immunodeficiency and autoimmunity. Therefore, regulation of T cell activation as well as maintenance of T cells in a quiescent state is an essential component of the balanced functioning of the immune system. The quiescent state may be due to a lack of activation signals or because of the presence of inhibition signals. In contrast to primary unstimulated T cells, which can enter the cell cycle and clonally expand after antigen-specific stimulation, quiescent T cells do not proliferate. Instead, they remain in a state of long term antigen-specific unresponsiveness, termed as T cell anergy.

The anergic state displays as an altered IL-2 gene expression. In anergic T cells, the activation signals (Eg antigens) are either absent or are insufficient to trigger a productive immune response. Presence of inhibition signals also gives rise to quiescence and anergy. The activation signals are not sufficient to trigger signaling pathways including ERK, JNK, NF-κB and NFAT that usually lead to the expression of the IL-2 gene. On the other hand, ERK, JNK, NF-κB, and NFAT pathways may also be inhibited by the presence of inhibitory molecules in the anergic state. Transducer of ERBB2 (TOB), a negative regulator of IL-2 transcription and T cell proliferation, is constitutively expressed in unstimulated peripheral blood T lymphocytes and selectively expressed in anergic T cells. Its expression is highest in unstimulated and anergic T cells and is reduced in activated T cells. TOB inhibits the process of costimulation of TCR signaling by CD28, thus repressing pathways that normally lead to IL-2 expression. Repression of IL-2 gene by TOB is also brought about by the interaction of TOB with SMAD proteins where TOB enhances SMAD binding to the -105 negative regulatory element of the IL-2 promoter. In T cells, SMADs mediate signals induced by TGF-β through its receptors TGF-βRII and TGF-βRI. The activated TGF-β receptors phosphorylate downstream targets SMAD2 and SMAD3, which form hetero-oligomeric complexes with SMAD4 and translocate to the nucleus. The SMAD complex downregulates IL-2 gene expression. (Updated 12/2020)