Involvement of the 4-1BB/4-1BBL Pathway in Control of Monocyte Numbers by Invariant NKT Cells

Abstract

4-1BB is expressed on invariant (i)NKT cells, but its role is unclear. We showed previously that iNKT cells are involved in control of monocyte numbers during influenza A virus (IAV) infection and now question the role of the 4-1BB costimulatory pathway in the cross-talk between these cells. We found that iNKT cells and monocytes interact to promote expression of 4-1BB and 4-1BBL, respectively. Blockade of 4-1BB/L pathway under resting coculture conditions increased apoptosis of iNKT cells and monocytes. However, activation of iNKT cells overrides this survival signal, causing marked apoptosis of monocytes independent of 4-1BB/L. Blocking 4-1BBL in alpha-galactosylceramide-activated iNKT–monocyte cocultures reduced iNKT proliferation and abrogated monocytic IL-12 production. In vivo, expression of 4-1BB and 4-1BBL is increased on iNKT cells and Ly6Chi monocytes, respectively, during IAV infection, and there were lower frequencies of apoptosing Ly6Chi monocytes in the blood of iNKT knockout mice and higher numbers of monocytes in lungs compared with infected wild-type mice. Adoptive transfer of iNKT cells into the lungs of these mice reduced lung Ly6Chi monocytes levels, even when iNKT cells were preincubated with 4-1BB blocking Abs. These findings suggest that under resting conditions, 4-1BB/L engagement during iNKT–monocyte interaction promotes survival of these cells. When iNKT cells are activated, whether by alpha-galactosylceramide or during IAV infection, iNKT cells induced apoptosis of monocytes via a 4-1BB/L–independent mechanism, reducing monocyte numbers. 4-1BB/L costimulation amplified monocyte-mediated proliferation of iNKT cells, indirectly providing a method for monocytes to control their own numbers during infection.

Porcine Invariant Natural Killer T Cells: Functional Profiling and Dynamics in Steady State and Viral Infections

“…An elevated fraction of CD27 − /CCR7 + iNKT cells, probably representing activated effector cells with de novo expression of CCR7 (63), further strengthens our hypothesis that iNKT cells exhibit a preactivated phenotype in naïve animals. A comparable phenotype has been shown in human and murine iNKT cells as well (13, 64–66). This preactivation is discussed as the result of a lower activation threshold of iNKT cells in comparison to cTC (67) or exposition to endogenous ligands (68).…”

“…This preactivation is discussed as the result of a lower activation threshold of iNKT cells in comparison to cTC (67) or exposition to endogenous ligands (68). Either way, preactivation of iNKT cells in vivo , in line with preformed cytokine mRNA (13), additionally emphasizes the ability of iNKT cells to respond immediately to stimuli (66). About half of all porcine iNKT cells expressed CCR7, which is critical for T cell extravasation and migration into T cell areas of secondary lymphoid tissues (69).…”

An Update on Anti-CD137 Antibodies in Immunotherapies for Cancer

“…The CD137/CD137L pathway also affects non-T cells in the immune system. The CD137/CD137L co-stimulation involves in controlling of monocyte numbers by amplification of monocyte-mediated proliferation of invariant NKT cells [23]. CD137 and/or CD137L agonists stimulate production of several inflammatory cytokines such as IL-6, TNF-α, and MCP-1 in adipocytes and macrophages [24].…”

Novel Discoveries in Immune Dysregulation in Inborn Errors of Immunity

“…First, activation of BCRs/TCRs is a prerequisite for CD137 expression, which enhances survival, proliferation and cytokine production (97,100). In invariant NKT (iNKT) cells, iNKTmonocyte interaction via CD137/CD137L promotes iNKT survival and proliferation and this interaction also affects monocytes survival (101). When CD137 is deficient, iNKT counts are reduced (102) due to at least partially the attenuated CD137/CD137L signal.…”