Biology subjects

de Boer, L.

Publications and source records attributed to de Boer, L..

4 recordsLinked to original sources

bioRxiv2022

T cell migration requires ion and water influx to regulate actin polymerization

Migration of T cells is essential for their ability to mount immune responses. Chemokine-induced T cell migration requires WNK1, a kinase that regulates ion influx into the cell. However, it is not known why ion entry is necessary for T cell movement. Here we show that signaling from the chemokine receptor CCR7 leads to activation of WNK1 and its downstream pathway at the leading edge of migrating CD4+ T cells, resulting in ion influx and water entry by osmosis. We propose that WNK1-induced water entry is required to swell the membrane at the leading edge, generating space into which actin filaments can polymerize, thereby facilitating forward movement of the cell. Given the broad expression of WNK1 pathway proteins, our study suggests that ion and water influx are likely to be essential for migration in many cell types, including leukocytes and metastatic tumor cells. One Sentence SummaryChemokine-induced migration of T cells requires water entry at the leading edge to facilitate actin polymerization.

immunology↗

bioRxiv2022

Water influx is required for CD4+ T cell activation and T cell-dependent antibody responses

Signaling from the T cell antigen receptor (TCR) on CD4+ T cells plays a critical role in adaptive immune responses by inducing T cell activation, proliferation, and differentiation. We demonstrate that WNK1, a kinase implicated in osmoregulation in the kidney, is required in T cells to support T-dependent antibody responses. WNK1-deficient CD4+ T cells are severely impaired in their ability to proliferate and to generate antigen-specific T follicular helper cells in response to immunization with a T-dependent antigen. We show that WNK1 and its downstream OXSR1 and STK39 kinases are required for TCR signaling in CD4+ T cells and for entry into cell cycle. Additionally, by preventing ATR activation, this pathway is required for T cells to progress from G2 into M phase of the cell cycle. Unexpectedly, we show that this WNK1 pathway regulates water influx, most likely through AQP3, which is required for TCR-induced signaling and cell cycle entry. Thus, TCR signaling via WNK1, OXSR1, STK39 and AQP3 leads to water entry that is essential for CD4+ T cell proliferation and hence T cell-dependent antibody responses. Given the broad expression of WNK1, WNK1-dependent water influx may be a common feature of mitogenic pathways in many cell types, both within the immune system and beyond. One Sentence SummaryT cell antigen receptor signaling via the WNK1 kinase causes water entry which is essential for CD4+ T cell proliferation.

immunology↗

bioRxiv2021

Motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function

Dopaminergic neurotransmission plays a pivotal role in appetitively motivated behavior in mammals, including humans. Notably, action and valence are not independent in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward. We have previously observed that the carriers of the DRD2/ANKK1 TaqIA A1 allele, that has been associated with reduced striatal dopamine D2 receptor expression, showed a diminished learning performance when required to learn response inhibition to obtain rewards, a finding that was replicated in two independent cohorts. In the present study, we first report a replication of this finding in a third independent cohort of 99 participants. Interestingly, after combining all three cohorts (total N = 281), exploratory analyses regarding the COMT Val108/158Met polymorphism suggest that homozygotes for the Met allele, which has been linked to higher prefrontal dopaminergic tone, show a lower learning bias. Our results corroborate the importance of genetic variability of the dopaminergic system in individual learning differences of action-valence interaction and, furthermore, suggest that motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function.

neuroscience↗

bioRxiv2019

Learning in anticipation of reward and punishment: Perspectives across the human lifespan

Pavlovian biases influence the interaction between action and valence by coupling reward seeking to action invigoration and punishment avoidance to action suppression. In this study we used an orthogonalised go/no-go task to investigate learning in 247 individuals across the human lifespan (7-80 years) to demonstrate that all participants, independently of age, demonstrated an influence of Pavlovian control. Computational modeling revealed peak performance in young adults was attributable to greater sensitivity to both rewards and punishment. However in children and adolescents an increased bias towards action but not reward sensitivity was observed. In contrast, reduced learning in midlife and older adults was accompanied with decreased reward sensitivity and especially punishment sensitivity. These findings reveal distinct learning capabilities across the human lifespan that cannot be probed using conventional go/reward no-go/punishment style paradigms that have important implications in life-long education.

neuroscience↗