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

Abstract

Follicular T-helper (T_FH) cells are a subpopulation of CD4+ lymphocytes, which within germinal centres, determine differentiation of B-cells into memory cells and antibody-secreting plasmacytes. T_FH are therefore critical players in vaccine-induced immunity. Study of T_FH 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 T_FH 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; T_FH (CD45RO+CXCR5+ICOS+PD1+) and pre-T_FH (CD45RO+CXCR5+ICOS+PD1-). In blood, transient increases in absolute numbers of these same populations were observed one week following vaccination (mean-fold-increase: T_FH = 6.3; P = 0.002. Pre-T_FH = 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 T_FH sub-population tallies with measurable B-cell antibody and blast changes following vaccination. This possibly reflects memory state, suggesting different roles of T_FH and pre-T_FH in primary and secondary responses. Further study of the function of T_FH in lymphoid tissue-should focus on these two dynamic populations.

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