Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon hepatitis B vaccination.

Esther Bartholomeus,Pieter Meysman,George Elias,Philippe Beutels,Pierre Van Damme,Marie-Paule Emonds,Geert Mortier,Aisha Souquette,Paul G Thomas,Nicolas De Neuter,Viggo Van Tendeloo,Benson Ogunjimi,Evelien Smits,Hilde Jansens,Hans De Reu,Kris Laukens,Arvid Suls,Nina Keersmaekers,Eva Lion

doi:10.7554/elife.68388

Abstract

Antigen recognition through the T cell receptor (TCR) αβ heterodimer is one of the primary determinants of the adaptive immune response. Vaccines activate naïve T cells with high specificity to expand and differentiate into memory T cells. However, antigen-specific memory CD4 T cells exist in unexposed antigen-naïve hosts. In this study, we use high-throughput sequencing of memory CD4 TCRβ repertoire and machine learning to show that individuals with preexisting vaccine-reactive memory CD4 T cell clonotypes elicited earlier and higher antibody titers and mounted a more robust CD4 T cell response to hepatitis B vaccine. In addition, integration of TCRβ sequence patterns into a hepatitis B epitope-specific annotation model can predict which individuals will have an early and more vigorous vaccine-elicited immunity. Thus, the presence of preexisting memory T cell clonotypes has a significant impact on immunity and can be used to predict immune responses to vaccination.

Highlights

Vaccinee cohort can be classified into three groups 117 Out of 34 vaccinees, 21 vaccinees seroconverted (an anti-hepatitis B (HB) titer above 10 IU/ml was 118 considered protective (Keating and Noble, 2003)) at day 60 and were classified as early119 converters; 9 vaccinees seroconverted at day 180 or day 365 and were classified as late120 converters; remaining 4 vaccinees had an anti-HBs antibody titer lower than 10 IU/ml at all time points following vaccination and were classified as non-converters (Figure 1 and Figure 1— figure supplement 1A). Members of Herpesviridae family might alter immune responses to vaccines (Furman et al, 2015)
We found no significant differences in cytomegalovirus (CMV), Epstein-Barr virus (EBV) or herpes simplex virus (HSV) seropositivity between the three groups in our cohort (Figure 1—figure supplement 1B)
We detected a significant increase in the breadth of HBsAg-specific TCRβ sequences at day 60 post-vaccination compared to pre-vaccination (Figure 2B and Figure 2—figure supplement 1D)

Summary

Results

Vaccinee cohort can be classified into three groups 117 Out of 34 vaccinees, 21 vaccinees seroconverted (an anti-HBs titer above 10 IU/ml was 118 considered protective (Keating and Noble, 2003)) at day 60 and were classified as early119 converters; 9 vaccinees seroconverted at day 180 or day 365 and were classified as late120 converters; remaining 4 vaccinees had an anti-HBs antibody titer lower than 10 IU/ml at all time points following vaccination and were classified as non-converters (Figure 1 and Figure 1— figure supplement 1A). The memory repertoire at day 60 shows that early-converters tend to have a higher breadth of putative HBsAg peptide-specific TCRβ, while late-converters tend to have relatively more putative false positives as per the normalization term (Figure 3B) The ratio of these two terms Rhbs shows a significant difference between early the late-converters at 214 day 60 (one-sided Wilcoxon-test P value= 0.0313, Figure 3C). A subset of both early and late-converters had detectable memory CD4 T cell responses prior to vaccination, we observed no significant differences in the frequencies of CD40L+4-1BB− and CD40L−4-1BB+ memory CD4 T cells between the two groups at day 0 (Figure 4D). An expanded subset of 4-1BB+CD45RA− TREG cells pre-vaccination is a prominent feature of a delayed and modest immune response to hepatitis B vaccine in our cohort. 295

Discussion

Findings

Methods