mTOR Promotes Antiviral Humoral Immunity by Differentially Regulating CD4 Helper T Cell and B Cell Responses

Abstract

mTOR has important roles in regulation of both innate and adaptive immunity, but whether and how mTOR modulates humoral immune responses have yet to be fully understood. To address this issue, we examined the effects of rapamycin, a specific inhibitor of mTOR, on B cell and CD4 T cell responses during acute infection with lymphocytic choriomeningitis virus. Rapamycin treatment resulted in suppression of virus-specific B cell responses by inhibiting proliferation of germinal center (GC) B cells. In contrast, the number of memory CD4 T cells was increased in rapamycin-treated mice. However, the drug treatment caused a striking bias of CD4 T cell differentiation into Th1 cells and substantially impaired formation of follicular helper T (Tfh) cells, which are essential for humoral immunity. Further experiments in which mTOR signaling was modulated by RNA interference (RNAi) revealed that B cells were the primary target cells of rapamycin for the impaired humoral immunity and that reduced Tfh formation in rapamycin-treated mice was due to lower GC B cell responses that are essential for Tfh generation. Additionally, we found that rapamycin had minimal effects on B cell responses activated by lipopolysaccharide (LPS), which stimulates B cells in an antigen-independent manner, suggesting that rapamycin specifically inhibits B cell responses induced by B cell receptor stimulation with antigen. Together, these findings demonstrate that mTOR signals play an essential role in antigen-specific humoral immune responses by differentially regulating B cell and CD4 T cell responses during acute viral infection and that rapamycin treatment alters the interplay of immune cell subsets involved in antiviral humoral immunity.IMPORTANCE mTOR is a serine/threonine kinase involved in a variety of cellular activities. Although its specific inhibitor, rapamycin, is currently used as an immunosuppressive drug in transplant patients, it has been reported that rapamycin can also stimulate pathogen-specific cellular immunity in certain circumstances. However, whether and how mTOR regulates humoral immunity are not well understood. Here we found that rapamycin treatment predominantly inhibited GC B cell responses during viral infection and that this led to biased helper CD4 T cell differentiation as well as impaired antibody responses. These findings suggest that inhibition of B cell responses by rapamycin may play an important role in regulation of allograft-specific antibody responses to prevent organ rejection in transplant recipients. Our results also show that consideration of antibody responses is required in cases where rapamycin is used to stimulate vaccine-induced immunity.

The influence of mTOR inhibitors on the incidence of CMV infection in high‐risk donor positive–recipient negative (D+/R−) kidney transplant recipients

“…This effect was dependent on virus priming and of CD4 + but not CD8 + T cells . Another experimental model showed that sirolimus interferes with mTOR activity altering the balance between Th1 and follicular T helper cells differentiation and specifically inhibiting B‐cell responses during primary lymphocytic choriomeningitis virus infection and protein immunization induced by B‐cell receptor antigen stimulation . Whether the observed trend toward lower recurrence rate is associated with mTOR inhibitor associated expansion of newly formed CMV‐specific CD8 + T cell clones and/or altered B‐cell response is unknown.…”

Mammalian target of rapamycin complex 1 signalling is essential for germinal centre reaction

“…The centre of B‐cell responses is the GC reaction, in which Tfh–GCB cell interactions are essential . Recently, the regulatory role of mTOR in Tfh–GCB cell interactions was clearly dissected . In fact, inactivation of mTORC1 signalling by rapamycin led to a halt of GCB cell responses and impaired helper CD4 T‐cell differentiation during viral infection .…”

“…Recently, the regulatory role of mTOR in Tfh–GCB cell interactions was clearly dissected . In fact, inactivation of mTORC1 signalling by rapamycin led to a halt of GCB cell responses and impaired helper CD4 T‐cell differentiation during viral infection . More recently, Tfh‐intrinsic mTOR signalling was shown to support Tfh cell differentiation and function by re‐modulating metabolism and promoting proliferation .…”

“…30 In fact, inactivation of mTORC1 signalling by rapamycin led to a halt of GCB cell responses and impaired helper CD4 T-cell differentiation during viral infection. 30 More recently, Tfh-intrinsic mTOR signalling was shown to support Tfh cell differentiation and function by re-modulating metabolism and promoting proliferation. 31,32 Indeed, all the evidence gained with our recent data suggest that mTOR signalling is critical for B-cell responses by supporting both Tfh and GCB cell differentiation/proliferation and ensuring an appropriate interaction between Tfh and GCB cells.…”

The metabolic spectrum of memory T cells

“…Although typically used as an immuno‐suppressant to prevent allograft rejection in transplant patients, rapamycin administration during T‐cell priming or expansion following vaccination can enhance T CM development . This strategy, while beneficial for vaccinations requiring T CM development, may be detrimental in vaccinations attempting to enhance T RM development or humoral immunity, both of which can be negatively impacted upon by rapamycin administration . So while there is great potential for manipulating memory T‐cell metabolism to improve human health, the key to successful therapies will be to further understand the biology of immune cell metabolism and to develop creative ways to deliver therapies in a targeted manner.…”