Cell intrinsic role of NF-κB-inducing kinase in regulating T cell-mediated immune and autoimmune responses

Abstract

NF-κB inducing kinase (NIK) is a central component of the noncanonical NF-κB signaling pathway. Although NIK has been extensively studied for its function in the regulation of lymphoid organ development and B-cell maturation, the role of NIK in regulating T cell functions remains unclear and controversial. Using T cell-conditional NIK knockout mice, we here demonstrate that although NIK is dispensable for thymocyte development, it has a cell-intrinsic role in regulating the homeostasis and function of peripheral T cells. T cell-specific NIK ablation reduced the frequency of effector/memory-like T cells and impaired T cell responses to bacterial infection. The T cell-conditional NIK knockout mice were also defective in generation of inflammatory T cells and refractory to the induction of a T cell-dependent autoimmune disease, experimental autoimmune encephalomyelitis. Our data suggest a crucial role for NIK in mediating the generation of effector T cells and their recall responses to antigens. Together, these findings establish NIK as a cell-intrinsic mediator of T cell functions in both immune and autoimmune responses.

The non-canonical NF-κB pathway in immunity and inflammation

“…Upon activation, CD4 + T cells differentiate into several subsets of effector T cells, including T helper 1 (T H 1), T H 2, T H 9, T H 17 and T FH cells, each with specialized helper or regulatory functions 125 . The non-canonical NF-κB pathway is dispensable for the initial activation of naive T cells through TCR signalling but is crucial for the in vivo generation and maintenance of effector and memory T cells 25,126,127 . As described above, non-canonical NF-κB signalling facilitates the differentiation of T FH cells involved in GC reactions, although this function of non-canonical NF-κB signalling is not T cell-intrinsic.…”

“…Recent studies using NIK-deficient mice and NF-κB2 Lym1 mice have also demonstrated a crucial role of the non-canonical NF-κB pathway in the induction of T H 1 and T H 17 effector cells in the neuroinflammation model experimental autoimmune encephalomyelitis (EAE) 25,126,127 . Compared with the situation in vivo, the non-canonical NF-κB pathway is much less important for T H 1 and T H 17 cell differentiation in an in vitro system, in which T cells are stimulated using agonistic TCR- and CD28-targeted antibodies in the presence of polarizing cytokines 25,100 .…”

“…Early studies suggested that non-canonical NF-κB signalling mediates T reg cell development indirectly through maintaining the integrity of the thymic stroma and the function of DCs 89,128 . However, more recent studies using bone marrow adoptive transfer and mice with a conditional depletion of NIK in T cells have demonstrated a T cell- intrinsic function for the non-canonical NF-κB pathway in regulating the peripheral maintenance of T cells 126,129 . T cell-specific deletion of NIK reduces the frequency and absolute number of T reg cells in the spleen and lymph nodes, although not in the thymus 126 .…”

“…However, more recent studies using bone marrow adoptive transfer and mice with a conditional depletion of NIK in T cells have demonstrated a T cell- intrinsic function for the non-canonical NF-κB pathway in regulating the peripheral maintenance of T cells 126,129 . T cell-specific deletion of NIK reduces the frequency and absolute number of T reg cells in the spleen and lymph nodes, although not in the thymus 126 . Thus, non-canonical NF-κB signalling has paradoxical roles in regulating T cell responses.…”

“…These include EAE, a widely used animal model of multiple sclerosis, which is a neuroinflammatory disease that is thought to involve autoreactive inflammatory T H 1 and T H 17 cells 168 . Several studies have demonstrated an essential role for NIK and non-canonical NF-κB signalling in mediating the pathogenesis of EAE 14,25,126,169 . Moreover, a recent genome-wide association study identified NIK as one of the candidate genes for multiple sclerosis susceptibility 170 .…”