Age-dependency of terminal ileum tissue resident memory T cell responsiveness profiles to S. Typhi following oral Ty21a immunization in humans

Jayaum S Booth, Eric Goldberg, Seema A Patil, Robin S Barnes, Bruce D Greenwald, Marcelo B Sztein, Jayaum S Booth, Eric Goldberg, Seema A Patil, Robin S Barnes, Bruce D Greenwald, Marcelo B Sztein

Abstract

Background: The impact of aging on the immune system is unequivocal and results in an altered immune status termed immunosenescence. In humans, the mechanisms of immunosenescence have been examined almost exclusively in blood. However, most immune cells are present in tissue compartments and exhibit differential cell (e.g., memory T cells -TM) subset distributions. Thus, it is crucial to understand immunosenescence in tissues, especially those that are exposed to pathogens (e.g., intestine). Using a human model of oral live attenuated typhoid vaccine, Ty21a, we investigated the effect of aging on terminal ileum (TI) tissue resident memory T (TRM) cells. TRM provide immediate adaptive effector immune responsiveness at the infection site. However, it is unknown whether aging impacts TRM S. Typhi-responsive cells at the site of infection (e.g., TI). Here, we determined the effect of aging on the induction of TI S. Typhi-responsive TRM subsets elicited by Ty21a immunization.

Results: We observed that aging impacts the frequencies of TI-lamina propria mononuclear cells (LPMC) TM and TRM in both Ty21a-vaccinated and control groups. In unvaccinated volunteers, the frequencies of LPMC CD103- CD4+ TRM displayed a positive correlation with age whilst the CD4/CD8 ratio in LPMC displayed a negative correlation with age. We observed that elderly volunteers have weaker S. Typhi-specific mucosal immune responses following Ty21a immunization compared to adults. For example, CD103+ CD4+ TRM showed reduced IL-17A production, while CD103- CD4+ TRM exhibited lower levels of IL-17A and IL-2 in the elderly than in adults following Ty21a immunization. Similar results were observed in LPMC CD8+ TRM and CD103- CD8+ T cell subsets. A comparison of multifunctional (MF) profiles of both CD4+ and CD8+ TRM subsets between elderly and adults also showed significant differences in the quality and quantity of elicited single (S) and MF responses.

Conclusions: Aging influences tissue resident TM S. Typhi-specific responses in the terminal ileum following oral Ty21a-immunization. This study is the first to provide insights in the generation of local vaccine-specific responses in the elderly population and highlights the importance of evaluating tissue immune responses in the context of infection and aging.

Trial registration: This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304 , Registered 29 May 2019 - Retrospectively registered).

Keywords: Aging; Oral vaccine; Terminal ileum LPMC; Tissue resident memory T cells; Ty21a; Vaccine-induced responses.

Conflict of interest statement

The authors declared no conflict of interest.

Figures

Fig. 1
Fig. 1
Age differences in frequencies of LPMC memory T cells isolated from Ty21a-vaccinated and unvaccinated volunteers. Comparison of TM subsets including TCM (CD62L+ CD45RA−), TEM (CD62L- CD45RA-), TEMRA (CD62L- CD45RA+), and Tnaive (CD62L+ CD45RA+) between adults (A; < 60 yrs.) and elderly (E; ≥60 yrs.) in TI-LPMC (a) CD4+ T and (b) CD8+ T cells obtained from Ty21a-vaccinated (red symbols) and unvaccinated (black symbols) volunteers. Frequencies of (c) TI-LPMC CD4+ CD103+ and CD4+ CD103- TRM and (d) TI-LPMC CD8+ CD69+ CD103+ (CD8+ TRM) and CD8+ CD69+ CD103- T cells were determined and compared between adults and elderly volunteers following Ty21a immunization. Median values for each group are denoted as horizontal black bars. Significant differences are denoted with *P < 0.05, **P < 0.005. Trends to exhibit significance values are indicated by their p-values
Fig. 2
Fig. 2
Age-dependent association of CD4+ and CD8+ TRM frequencies and T cell subsets in terminal ileum mucosa following oral Ty21a immunization. Correlations between age and the frequencies of tissue resident T cells were determined using Pearson’s analysis. a Unvaccinated LPMC CD4+ CD103+ TRM (black symbols), and CD4+ CD103- TRM (blue symbols), as well as Ty21a-vaccinated LPMC CD4+ CD103+ TRM (green symbols) and CD4+ CD103- TRM (red symbols) frequencies were correlated to the age of the volunteers. b Similarly, unvaccinated LPMC CD8+ TRM cells (black symbols), and CD8+ CD103- T cells (blue symbols), and Ty21a-vaccinated LPMC CD8+ TRM (green symbols) and CD8+ CD103- T cells (red symbols) frequencies were correlated to the age of the volunteers. Significant correlations are denoted with * P < 0.05. Trends to exhibit significant correlations are indicated by their p-values
Fig. 3
Fig. 3
Age-dependent correlation of the ratios of CD4 to CD8 cells among CD3+ T cells in peripheral blood and in CD103+ and CD103- subsets in LPMC isolated from TI biopsies. The ratio of CD4 to CD8 cells were correlated to age in (a) PBMC CD3+ T cells, (b) LPMC CD3+ T cells, (c) LPMC CD3+ CD103+ T cells and (d) LPMC CD3+ CD103- T cells. Significant correlations and trends to show correlations are indicated with * and/or their p-value, respectively
Fig. 4
Fig. 4
Multifunctional (MF) and single-expressing (S) S. Typhi-specific CD4+ and CD8+ TEM responses following Ty21a immunization. Net S. Typhi-specific CD4+ and CD8+ TEM responses were calculated using the FCOM function of Winlist and stratified into S and MF responses. Comparison of TI LPMC S. Typhi-specific (a) CD4+ TEM S, (b) CD4+ TEM MF, (c) CD8+ TEM S and (d) CD8+ TEM MF responses between Ty21a-vaccinated (red symbols) and unvaccinated (black symbols) volunteers were determined with significant differences shown (*P < 0.05). Trends to exhibit significance values are indicated by their p-values. Horizontal black bars represent median values
Fig. 5
Fig. 5
Multifunctional (MF) and single-expressing (S) S. Typhi-specific CD4+ TEM responses in adults compared to elderly volunteers following Ty21a immunization. Net S. Typhi-specific CD4+ TEM responses were calculated using the FCOM function of Winlist and stratified into single-expressing (S) and MF responses. Comparison of TI LPMC S. Typhi-specific CD4+ TEM responses between adults (A- < 60 yrs.) and elderly (E- ≥ 60 yrs.) volunteers in (a) CD107a+, (b) INF-γ+, (c) TNF-α+, (d) IL-17A+, (e) IL-2+, and (f) MIP-1β + S and MF responses in Ty21a-vaccinated (red symbols) and unvaccinated (black symbols) volunteers with significant differences shown (*P < 0.05). Trends to exhibit significance values are indicated by their p-values. Horizontal black bars represent median values
Fig. 6
Fig. 6
LPMC multifunctional (MF) and single-expressing (S) S. Typhi–specific CD8+ TEM responses in adults compared to elderly volunteers following Ty21a immunization. Net S. Typhi-specific CD8+ TEM responses were calculated using the FCOM function of Winlist and stratified into S and MF responses. Comparison of TI LPMC S. Typhi-specific CD8+ TEM responses in (a) CD107a+, (b) INF-γ, (c) TNF-α+, (d) IL-17A+, (e) IL-2+, and (f) MIP-1β + S and MF between adults (A- < 60 yrs.) and elderly (E- ≥ 60 yrs.) volunteers that were either orally vaccinated with Ty21a (red symbols) or unvaccinated (black symbols). Trends to exhibit significant values are indicated by their p-values. Horizontal black bars represent median values
Fig. 7
Fig. 7
S. Typhi-specific responses of TI LPMC CD69+ CD103+ CD4+ TRM and CD69+ CD103- CD4+ TRM subsets in healthy adults and elderly volunteers following oral Ty21a-immunization. The net percentages of S. Typhi-specific responses (IFNγ+, IL-17A+, IL-2+, and TNFα+) in (a) CD69+ CD103+ CD4+ TRM and (b) CD69+ CD103- CD4+ TRM subsets were compared between adults (A- < 60 yrs.) and elderly (E- ≥ 60 yrs.) volunteers who were either Ty21a-vaccinated (red symbols) or unvaccinated (black symbols) with significant differences (*P < 0.05) indicated. Trends to exhibit significance are indicated by their p-values. Horizontal bars (black) represent median values
Fig. 8
Fig. 8
S. Typhi-specific responses of terminal ileum LPMC CD8+ TRM and CD8+ CD69+ CD103- T cell subsets in healthy adults and elderly volunteers following oral Ty21a immunization. The net percentages of S. Typhi-specific responses (IFNγ+, IL-17A+, IL-2+, and TNFα+) in (a) CD8+ TRM and (b) CD8+ CD69+ CD103- T cell subsets were compared between adults (A- < 60 yrs) and elderly (E- ≥ 60 yrs.) volunteers who were either Ty21a-vaccinated (red symbols) or unvaccinated (black symbols). Significant differences (*P < 0.05; **P < 0.005; ***P < 0.0005) are indicated. Trends to exhibit significance are indicated by their p-values. Horizontal bars (black) represent median values

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Source: PubMed

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