Liver-resident CD8+ T cells are highly motile cells that patrol the vasculature and provide protection against liver pathogens. A key question is: how can these liver CD8+ T cells be simultaneously present in the circulation and tissue-resident? Because liver-resident T cells do not express CD103 - a key integrin for T cell residence in epithelial tissues - we investigated other candidate adhesion molecules. Using intra-vital imaging we found that CD8+ T cell patrolling in the hepatic sinusoids is dependent upon LFA-1-ICAM-1 interactions. Interestingly, liver-resident CD8+ T cells up-regulate LFA-1 compared to effector-memory cells, presumably to facilitate this behavior. Finally, we found that LFA-1 deficient CD8+ T cells failed to form substantial liver-resident memory populations following Plasmodium or LCMV immunization. Collectively, our results demonstrate that it is adhesion through LFA-1 that allows liver-resident memory CD8+ T cells to patrol and remain in the hepatic sinusoids.
Protective high-affinity antibody responses depend on competitive
selection of B cells carrying somatically mutated B-cell receptors by follicular
helper T (TFH) cells in germinal centres. The rapid T-B-cell
interactions that occur during this process are reminiscent of neural synaptic
transmission pathways. Here we show that a proportion of human TFH
cells contained dense-core granules marked by chromogranin B, which are normally
found in neuronal presynaptic terminals storing catecholamines such as dopamine.
TFH cells produce high amounts of dopamine and released it upon
cognate interaction with B cells. Dopamine causes rapid translocation of
intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as
ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and
chromogranin B granules at the human TFH cell synapse and increases
the synapse area. Mathematical modelling suggests that faster dopamine-induced
T-B-cell interactions increase total germinal centre output and accelerate it by
days. Delivery of neurotransmitters across the T-B-cell synapse may be
advantageous in the face of infection.
The repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) is a major vaccine antigen because it can be targeted by parasite neutralizing antibodies; however, little is known about this interaction. We used isothermal titration calorimetry, X-ray crystallography and mutagenesis-validated modeling to analyze the binding of a murine neutralizing antibody to Plasmodium falciparum CSP. Strikingly, we found that the repeat region of CSP is bound by multiple antibodies. This repeating pattern allows multiple weak interactions of single FAB domains to accumulate and yield a complex with a dissociation constant in the low nM range. Because the CSP protein can potentially cross-link multiple B cell receptors (BCRs) we hypothesized that the B cell response might be T cell independent. However, while there was a modest response in mice deficient in T cell help, the bulk of the response was T cell dependent. By sequencing the BCRs of CSP-repeat specific B cells in inbred mice we found that these cells underwent somatic hypermutation and affinity maturation indicative of a T-dependent response. Last, we found that the BCR repertoire of responding B cells was limited suggesting that the structural simplicity of the repeat may limit the breadth of the immune response.
Summary
Antibodies targeting the NANP/NVDP repeat domain of the
Plasmodium falciparum
circumsporozoite protein (CSP
Repeat
) can protect against malaria. However, it has also been suggested that the CSP
Repeat
is a decoy that prevents the immune system from mounting responses against other domains of CSP. Here, we show that, following parasite immunization, B cell responses to the CSP
Repeat
are immunodominant over responses to other CSP domains despite the presence of similar numbers of naive B cells able to bind these regions. We find that this immunodominance is driven by avid binding of the CSP
Repeat
to cognate B cells that are able to expand at the expense of B cells with other specificities. We further show that mice immunized with repeat-truncated CSP molecules develop responses to subdominant epitopes and are protected against malaria. These data demonstrate that the CSP
Repeat
functions as a decoy, but truncated CSP molecules may be an approach for malaria vaccination.
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