Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age

Abstract

T cell-dependent B-cell responses decline with age, suggesting defective CD4 T-cell function. CD4 memory T cells from individuals older than 65 y displayed increased and sustained transcription of the dual-specific phosphatase 4 (DUSP4) that shortened expression of CD40-ligand (CD40L) and inducible T-cell costimulator (ICOS) (both P < 0.001) and decreased production of IL-4, IL-17A, and IL-21 (all P < 0.001) after in vitro activation. In vivo after influenza vaccination, activated CD4 T cells from elderly individuals had increased DUSP4 transcription (P = 0.002), which inversely correlated with the expression of CD40L (r = 0.65, P = 0.002), ICOS (r = 0.57, P = 0.008), and IL-4 (r = 0.66, P = 0.001). In CD4 KO mice reconstituted with DUSP4 OT-II T cells, DUSP4 had a negative effect on the expansion of antigen-specific B cells (P = 0.003) and the production of ovaspecific antibodies (P = 0.03) after immunization. Silencing of DUSP4 in memory CD4 T cells improved CD40L (P < 0.001), IL-4 (P = 0.007), and IL-21 (P = 0.04) expression significantly more in the elderly than young adults. Consequently, the ability of CD4 memory T cells to support B-cell differentiation that was impaired in the elderly (P = 0.004) was restored. Our data suggest that increased DUSP4 expression in activated T cells in the elderly in part accounts for defective adaptive immune responses.immunosenescence | signaling | aging W ith increasing age, the ability of the immune system to protect against new antigenic challenges or control chronic infections erodes (1, 2). Incidence and severity of viral infections increase, and the response to prophylactic vaccination declines. More than 90% of all influenza-related deaths in the United States occur in the elderly (3). Vaccine-induced protection for influenza infection is between 20% and 50% in the elderly dependent on age and study compared with ∼90% in young adults (4). In a review of 31 vaccine antibody response studies, the odds ratios to seroconvert or develop seroprotective antibody titers in elderly vs. young adults ranged from 0.24 to 0.59 (5). Epidemiological studies did not find an impact of the increasing compliance with annual flu vaccination on seasonal mortality between 1968 and 2001, further questioning their efficacy (6). The mechanisms accounting for this defective vaccine response have not been identified but likely involve B as well as T cells. Given that the vast majority of adults have had previous exposure to influenza and that antigenic drifts and shifts of the influenza virus involve B-rather than T-cell epitopes, the T-cell defect seems to lie in CD4 memory rather than naïve T-cell function (7). A decline in the frequency and function of virusspecific memory CD4 T cells is also responsible for the increasing incidence of herpes zoster with age caused by the Varicella zoster virus (VZV) (8). VZV is an α-herpes virus that causes chicken pox in children and establishes latency in sensorineural ganglions. On reactivation of VZV from latency, virus is transported along neuronal a...

DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia

“…[29][30][31] We also found that the cell cycle inhibitors CDKN1A, GADD45A, and FAS, all of which are upregulated with increasing age in T cells, 28 were also upregulated in ICL. A striking observation was the marked downregulation in ICL CD4…”

Causes, consequences, and reversal of immune system aging

“…As previously discussed, class switch recombination is impaired in aging murine and human B cells due to decreased expression of enzymes such as AID (53,84). Aberrant T cell signaling has also been associated with aging (48,85), and the list of dysregulated genes continues to grow, as indicated by several recent reports (86)(87)(88), two of which focused on altered expression of dual specific phosphatases (DUSPs). DUSPs deactivate target kinases, including those in the MAPK pathway whose activity is critical for T cell activation, differentiation, and cytokine production.…”

“…DUSPs deactivate target kinases, including those in the MAPK pathway whose activity is critical for T cell activation, differentiation, and cytokine production. One study reported the induction and sustained transcription of DUSP4 in activated CD4 + memory T cells from humans 65 and older, which correlated with their altered cytokine production and an impaired ability to provide help for B cells (87). A subsequent report from the same laboratory described the increased expression of DUSP6 in naive CD4 + human T cells, which resulted in activation of a lower fraction of Th cells, particularly in response to low-affinity stimuli (88).…”

Aging of the Immune System. Mechanisms and Therapeutic Targets

“…aging T cells is the dual-specificity protein phosphatase 4 (DUSP4) (47), which negatively regulates members of the MAPK superfamily, in particular ERK1, ERK2, and JNK. ERK is also subject to increased negative regulation by another dual-specificity protein phosphatase, DUSP6 (48).…”

“…ERK is a key regulator of the T-cell receptor signaling cascade, and its dephosphorylation by DUSP4 and DUSP6 functions as a suppressive mechanism, weakening the T-cell receptor-induced signal and dampening T-cell function. Old, DUSP4 high T cells lose their ability to provide helper function for antibody-forming B cells, thus undermining protective immunity (47).…”