Fingolimod can act as a facilitator to establish the primary T-cell response with reduced need of adjuvants

The CD8⁺ T-cell response is an essential part of the adaptive immunity. Adjuvants are routinely required for priming of T cells against antigens encountered in lymph nodes (LNs) to generate antigen-specific immunity but may concomitantly trigger unexpected inflammatory responses. Sphingosine-1-phosphate (S1P) induces transient desensitization of S1P receptors on LN T cells and temporarily blocks their egress, leading to prolonged intranodal retention that allows effective immunosurveillance and increases the chance of priming. In light of the regulatory role of S1P in T-cell migration, we here develop a strategic approach to the T-cell priming with protein vaccine containing low-dose TLR-based adjuvants (LDAV) to induce antigen-specific CD8⁺ T cell responses as efficiently as using regular dose adjuvants in vaccine (RDAV). We found that when combined with one low dose of the S1P analog fingolimod administered into the same vaccination site posteriorly at a specific time, LDAV can elicit a primary response that reaches the level of that induced by RDAV with respect to the response magnitude and functionality. Time-course studies indicate that LDAV and fingolimod in combination act to mimic the expansion kinetics of RDAV-primed antigen-specific CD8⁺ T cells. Further, intranodal accumulation of cDC1 is markedly enhanced in mice receiving the combination vaccination despite the decrease in adjuvant use. Of particular note is the marginal cutaneous inflammation at the injection site, indicating an added benefit of using fingolimod. Therefore, fingolimod as a nonadjuvant agent essentially facilitates antigen-specific T-cell priming with reduced need of adjuvants and minimized adverse reactions.