The University of Southampton
University of Southampton Institutional Repository

The role of the lymph node in the establishment of an adaptive immune response to vaccination

The role of the lymph node in the establishment of an adaptive immune response to vaccination
The role of the lymph node in the establishment of an adaptive immune response to vaccination
Follicular T-helper (TFH) cells are a subpopulation of CD4+ lymphocytes, which within germinal centres, determine differentiation of B-cells into memory cells and antibody-secreting plasmacytes. TFH are therefore critical players in vaccine-induced immunity. Study of TFH has been limited, as they are thought to be tissue resident cells, which do not normally re-circulate. While accessing blood is straightforward, access to lymph node tissue responding to vaccine is very limited. Therefore data on functions of tissue-resident human TFH cells remains sparse.

This thesis details establishment of an ethically approved peri-surgical window of opportunity study and development of novel tissue processing techniques and laboratory assays designed to overcome this hurdle. I randomized 42 consenting breast cancer patients due to undergo sentinel lymph node biopsy to be vaccinated with combined tetanus/diphtheria/polio vaccine ipsilateraly, contralateraly or not at all prior to surgery. A vaccine draining, non-sentinel node was studied in the context of vaccine-specific antibody and circulating lymphocyte response over the seven weeks following vaccination.

Only lymph nodes draining the ipsilateral vaccine site were enriched for two CD4+derived populations; TFH (CD45RO+CXCR5+ICOS+PD1+) and pre-TFH (CD45RO+CXCR5+ICOS+PD1-). In blood, transient increases in absolute numbers of these same populations were observed one week following vaccination (mean-fold-increase: TFH = 6.3; P = 0.002. Pre-TFH = 4.0; P=0.002). In contrast a related population (CD45RO+CXCR5+ICOS-PD1+) showed no enrichment within vaccine-draining nodes or changes in circulating numbers post-vaccine.

Total IgG, IgM and IgG1-4 isotype immunoglobulin vaccine response was assessed. Response correlated with predominant cell-type increase in blood: CD45RO+CXCR5+ICOS+PD1- were prevalent in slow-responders, correlating with increases in immunoglobulin-switched plasmablasts (r = 0.90; 95%CI 0.74-0.97. P<0.0001), whereas CD45RO+CXCR5+ICOS+PD1+ were prominent in fast-responders, associated with increasing unswitched plasmablasts (r = 0.79; 95%CI 0.51-0.90. P<0.0001) and plasma cells (r = 0.57; 95%CI 0.17-0.81. P = 0.007).

Dichotomisation of response according TFH sub-population tallies with measurable B-cell antibody and blast changes following vaccination. This possibly reflects memory state, suggesting different roles of TFH and pre-TFH in primary and secondary responses. Further study of the function of TFH in lymphoid tissue-should focus on these two dynamic populations.
University of Southampton
Layfield, David Michael
9e0fbad6-2b96-468b-bf4e-366e92d5dcb4
Layfield, David Michael
9e0fbad6-2b96-468b-bf4e-366e92d5dcb4
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Cutress, Ramsey
68ae4f86-e8cf-411f-a335-cdba51797406

Layfield, David Michael (2016) The role of the lymph node in the establishment of an adaptive immune response to vaccination. University of Southampton, Doctoral Thesis, 458pp.

Record type: Thesis (Doctoral)

Abstract

Follicular T-helper (TFH) cells are a subpopulation of CD4+ lymphocytes, which within germinal centres, determine differentiation of B-cells into memory cells and antibody-secreting plasmacytes. TFH are therefore critical players in vaccine-induced immunity. Study of TFH has been limited, as they are thought to be tissue resident cells, which do not normally re-circulate. While accessing blood is straightforward, access to lymph node tissue responding to vaccine is very limited. Therefore data on functions of tissue-resident human TFH cells remains sparse.

This thesis details establishment of an ethically approved peri-surgical window of opportunity study and development of novel tissue processing techniques and laboratory assays designed to overcome this hurdle. I randomized 42 consenting breast cancer patients due to undergo sentinel lymph node biopsy to be vaccinated with combined tetanus/diphtheria/polio vaccine ipsilateraly, contralateraly or not at all prior to surgery. A vaccine draining, non-sentinel node was studied in the context of vaccine-specific antibody and circulating lymphocyte response over the seven weeks following vaccination.

Only lymph nodes draining the ipsilateral vaccine site were enriched for two CD4+derived populations; TFH (CD45RO+CXCR5+ICOS+PD1+) and pre-TFH (CD45RO+CXCR5+ICOS+PD1-). In blood, transient increases in absolute numbers of these same populations were observed one week following vaccination (mean-fold-increase: TFH = 6.3; P = 0.002. Pre-TFH = 4.0; P=0.002). In contrast a related population (CD45RO+CXCR5+ICOS-PD1+) showed no enrichment within vaccine-draining nodes or changes in circulating numbers post-vaccine.

Total IgG, IgM and IgG1-4 isotype immunoglobulin vaccine response was assessed. Response correlated with predominant cell-type increase in blood: CD45RO+CXCR5+ICOS+PD1- were prevalent in slow-responders, correlating with increases in immunoglobulin-switched plasmablasts (r = 0.90; 95%CI 0.74-0.97. P<0.0001), whereas CD45RO+CXCR5+ICOS+PD1+ were prominent in fast-responders, associated with increasing unswitched plasmablasts (r = 0.79; 95%CI 0.51-0.90. P<0.0001) and plasma cells (r = 0.57; 95%CI 0.17-0.81. P = 0.007).

Dichotomisation of response according TFH sub-population tallies with measurable B-cell antibody and blast changes following vaccination. This possibly reflects memory state, suggesting different roles of TFH and pre-TFH in primary and secondary responses. Further study of the function of TFH in lymphoid tissue-should focus on these two dynamic populations.

Text
Layfield final thesis COMBINED - Version of Record
Available under License University of Southampton Thesis Licence.
Download (49MB)

More information

Published date: November 2016

Identifiers

Local EPrints ID: 427143
URI: http://eprints.soton.ac.uk/id/eprint/427143
PURE UUID: b357528f-79a7-4ccd-b5d7-c6929ee39050

Catalogue record

Date deposited: 03 Jan 2019 17:30
Last modified: 13 Mar 2019 17:42

Export record

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×