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Relationship: 2004
Title
Suppression of T cell activation leads to Impairment of TDAR
Upstream event
Downstream event
AOPs Referencing Relationship
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | High |
Normal T cell and B cell function is indispensable for host defense mechanism. T cells are activated when they recognize antigens and induce T-cell dependent antibody response (TDAR) by secreting various cytokines as described below (Abbas et al. 2020). Therefore, suppression of T cell activation leads to impairment of TDAR. Various Interleukins (ILs) such as IL-2 and IL-4 are produced and secreted by activated helper T cells and play important roles in the development of TDAR. IL-4 affects maturation and class switching of B cells as well as proliferation, IL-2 promotes differentiation of B cells through IL-2 receptors and stimulates the activated T cell into T cell called Th2 cell. Therefore, suppressed production of IL-2 and IL-4 impairs T cell dependent antibody production (Alberts et al. 2008).
T cells, B cells, and antigen-presenting cells such as dendritic cells are involved in inducing and developing of TDAR. Thus, changes in any of these immune cell populations can influence TDAR. Activated T cell-derived cytokines play important roles in the development of TDAR. Among them, IL-2 promotes proliferation of B cells, and IL-4 affects maturation and class switching of B cells as well as proliferation, both of which induces/enhances T cell dependent antibody production.
Thus, suppressing the production of IL-2, IL-4, and other cytokines in T cells reduces stimulation of B cells including proliferation, activation, and class switching, and leading to impairment of TDAR. Therefore, suppressing the production of these B-cell-related cytokines appears to be the main factor in impairment of TDAR by inhibitors of T-cell–dependent-antibody production.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
IL-2 affects multiple populations of immune cells expressing IL-2 receptors, while IL-4 mainly acts on B cells. Therefore, reduced production of both IL-2 and IL-4 might certainly induce suppression of TDAR; however, there remains some possibility of additional suppression of other immune functions.
Luster et al (1993) demonstrated that Concanavalin A response of splenocytes showed the linear dose-response relationship with the host resistnace to Listeria monocytogenes or Streptococcus pneumoniae.
Response-response Relationship
Cynomolgus monkeys treated wth CsA at 50 mg/kg BID showed suppression of IL-2 and IL-4 production and inhibition of SRBC-specific IgM and IgG in TDAR (Gaida K. 2015).
In the blocking of IL-4 receptor in mice by dupilumab (anti-IL-4/13R antibody) at 25 mg/kg of twice weekly subcutaneous administration for 4weeks, IgE production was suppressed to about 1/100 and antigen specific IgG1 production was suppressed to
about 1/200 (Sanofi K.K. 2018).
In the inhibition of IL-4 production in mice by suplatast tosilate at 10, 20, 50 and 100 mg/kg of oral administration for 5 days, antigen specific IgE production was suppressed from about 1/10 to 1/100 (Taiho Pharmaceutical 2013). In human T cell culture by suplatast tosilate at the concentration of 10 µg/mL, antigen specific IgE production after 10 days was suppressed from 56 to 72% and IL-4 production after 3 days was suppressed from 58 to 76% (Taiho Pharmaceutical 2013).
As for IL-2 and antibody production, in vitro T-cell-induced polyclonal B cell activation to produce antibody was inhibited with anti-IL-2 and anti-IL-2R antibodies. That is, murine small resting B cells, cultured with irradiated hapten-specific TH1 clone, were induced to enter cell cycle at 2 days and to secret antibody at 5 days. An anti-IL-2 and anti-IL-2R antibodies completely inhibited this T-cell dependent antibody production (Owens T, 1991).
In the human T-B cell co-culture stimulated with anti-CD3 monoclonal antibody, CNIs of FK506 and CsA lowered the m-RNA levels of T-cell cytokines at 8h post-stimulation including IL-2 and IL-4 at 1.0ng/mL (1.24nM) FK506 or 100ng/mL (90.7nM) CsA and
inhibited IgM and IgG productions after 9 days at 0.3 and 1.0ng/mL FK506 and 50 and 100ng/mL CsA (Heidt S. 2010).
Time-scale
In CsA-treatment for 24 days at 50 mg/kg BID, cynomolgus monkeys showed suppression of IL-2 and IL-4 production and inhibition of SRBC-specific IgM and IgG in TDAR (Gaida K. 2015).
In human T cell culture, suplatast tosilate inhibits IL-4 production after 3 days and antigen specific IgE production after 10 days (Taiho Pharmaceutical 2013).
In the human T-B cell co-culture, CNIs of FK506 and CsA lowered the m-RNA levels of IL-2 and IL-4 at 8h post-stimulation and inhibited IgM and IgG productions after 9 days (Heidt S. 2010).
Known Feedforward/Feedback loops influencing this KER
At present, no evidence is found.