Members of the Trem receptor family (Triggering receptor expressed on myeloid cells) fine-tune inflammatory responses. We previously identified one of these receptors, called Trem-like 4 (Treml4), expressed mainly in the spleen, and at high levels by CD8α+ DCs and macrophages. Like other Trem family members, Treml4 has an immunoglobulin-like extracellular domain and a short cytoplasmic tail that associates with the adaptor DAP12. To follow our initial results that Treml4-Fc fusion proteins bind necrotic cells, we now generated a knock out mouse to assess the role of Treml4 in the uptake and presentation of dying cells in vivo. Loss of Treml4 expression did not impair uptake of dying cells by CD8α+ DCs or cross-presentation of cell-associated antigen to CD8+ T cells, suggesting overlapping function between Treml4 and other receptors in vivo. To further investigate Treml4 function, we took advantage of a newly generated mAb against Treml4, and engineered its heavy chain to express 3 different antigens, i.e., ovalbumin, HIV GAGp24 and the extracellular domain of the breast cancer protein HER2. Ovalbumin directed to Treml4 was efficiently presented to CD8+ and CD4+ T cells in vivo. Anti-Treml4-GAGp24 mAbs, given along with a maturation stimulus, induced Th1 antigen-specific responses which were not observed in Treml4 knock out mice. Also, HER2 targeting using anti-Treml4 mAbs elicited combined CD4+ and CD8+ T cell immunity, and both T cells participated in resistance to a transplantable tumor. Therefore, Treml4 participates in antigen presentation in vivo, and targeting antigens with anti-Treml4 antibodies enhances immunization of otherwise naïve mice.