Memory-like CD8⁺ T cells generated during homeostatic proliferation defer to antigen-experienced memory cells

Naïve T cells proliferate in response to lymphopenia and acquire the phenotypic and functional qualities of memory T cells, providing enhanced protection against infection. How well 'memory-like' T cells generated during lymphopenia-induced homeostatic proliferation (HP-memory) differentiate into secondary memory cells and compete with antigen-experienced 'true-memory' cells is previously unknown. We found that CD8⁺ HP-memory T cells generated robust responses upon infection and produced a secondary memory population comparable to true-memory cells in the absence of competition. However, when true-memory and HP- memory T cells competed during infection, HP-memory cells contributed less to the effector population, contracted earlier and formed fewer secondary memory cells than the true-memory cells, despite earlier expansion. The HP- memory T cells can in turn outcompete naïve T cells during the immune response, revealing the existence of a memory T cell response hierarchy. Furthermore, HP- and true-memory cells demonstrated distinct localization within the spleen during infection, indicating differential access to signals necessary for secondary memory formation. We attempted to rescue the HP-memory cells during the course of competition by administering saturating amounts of antigen and cytokine such as IL-7 and IL-15, but were not successful, indicating that they were not competing for those factors. Secondary memory derived from the HP-memory cells continued to defer to secondary memory derived from the true-memory cells in the course of the tertiary infection, indicating that the nature of the HP programming could not be overcome with antigen exposure. Thus, HP-memory T cells provide protection without compromising the true-memory population. This is of clinical relevance as HP-memory T cells can arise due to a multitude of medical causes. Their natural presence as part of the immune compartment will not contribute to the erosion of the established true-memory populations derived from vaccinations and prior infections. HP-memory cells are not an exact substitute for memory, but serve as a viable source of protection from pathogenic invasion. Differences in HP-and true-memory T cells may reveal the basis for competition for limited resources within the memory T cell compartmen