Abstract
Vaccination strategy that induce efficient antibody responses polytopically in most lymph nodes (LNs) against infections has not been established yet. Because donor-specific blood transfusion induces anti-donor class I MHC antibody production in splenectomized rats, we examined the mechanism and significance of this response. Among the donor blood components, T cells were the most efficient immunogens, inducing recipient T cell and B cell proliferative responses not only in the spleen, but also in the peripheral and gut LNs. Donor T cells soon migrated to the splenic T cell area and the LNs, with a temporary significant increase in recipient NK cells. XCR1+ resident dendritic cells (DCs), but not XCR1− DCs, selectively phagocytosed donor class I MHC+ fragments after 1 day. After 1.5 days, both DC subsets formed clusters with recipient CD4+ T cells, which proliferated within these clusters. Inhibition of donor T cell migration or depletion of NK cells by pretreatment with pertussis toxin or anti-asialoGM1 antibody, respectively, significantly suppressed DC phagocytosis and subsequent immune responses. Three allogeneic strains with different NK activities had the same response but with different intensity. Donor T cell proliferation was not required, indicating that the graft vs. host reaction is dispensable. Intravenous transfer of antigen-labeled and mitotic inhibitor-treated allogeneic, but not syngeneic, T cells induced a polytopical antibody response to labeled antigens in the LNs of splenectomized rats. These results demonstrate a novel mechanism of alloresponses polytopically in the secondary lymphoid organs (SLOs) induced by allogeneic T cells. Donor T cells behave as self-migratory antigen ferries to be delivered to resident XCR1+ DCs with negligible commitment of migratory DCs. Allogeneic T cells may be clinically applicable as vaccine vectors for polytopical prophylactic antibody production even in asplenic or hyposplenic individuals.
Highlights
For vaccination against infectious agents, efficient antigen delivery to sites of T cell priming within the recipient secondary lymphoid organs (SLOs) is crucial for the successful production of neutralizing antibodies [1]
When fresh blood of ACI rats was transfused to Lewis rats, an equivalent number of purified T cells and white blood cells (WBCs) fractions present in the blood induced a comparable level of Donor-specific transfusion (DST) antibodies (Figure 1A)
With anti-asialo GM1 antibody (Ab) treatment, the numbers of recipient CFSE+ phagocytic dendritic cells (DCs) and NK cells were significantly reduced compared to non-treated control. (G) Phenotype of CFSE+ phagocytic DCs in the peripheral lymph nodes (LNs). Note that they were XCR1+signal regulatory protein 1 α (SIRP1α)−, similar as those of spleen. These results indicate that allogeneic T cells induced a DST antibody response in the peripheral LNs in a similar manner as in the spleen, dependent on the NK response and phagocytosis by XCR1+ DCs in ACI to Lewis rat combination
Summary
For vaccination against infectious agents, efficient antigen delivery to sites of T cell priming within the recipient secondary lymphoid organs (SLOs) is crucial for the successful production of neutralizing antibodies [1]. Major sites of immune response after vaccination are generally the spleen and regional LNs. Because the spleen is crucial for antibody production against antigens in the blood, patients with an absent or dysfunctional spleen are at increased risk of severe infection. Intense vaccination against encapsulated bacteria and pandemic viruses as well as prophylactic antibiotics therapy are strongly recommended for splenectomized patients [4], and the development of a vaccination method for these patients that induces an efficient antibody response in other SLOs is a clinically important issue. Since a normal young adult body contains up to 450 LNs [5], the antigen targeting to DCs polytopically in most LNs would be able to promote intense antibody production
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