CD4+ T Cell Persistence and Function after Infection Are Maintained by Low-Level Peptide:MHC Class II Presentation

Abstract

CD4+ memory-phenotype T cells decline over time when generated in response to acute infections cleared by other components of the immune system. It was therefore of interest to assess the stability of CD4+ T cells during a persistent Salmonella infection, which is typical of persistent phagocytic infections that are controlled by this lymphocyte subset. We found that CD4+ T cells specific for Salmonella peptide:MHCII ligands were numerically stable for greater than a year after initial oral infection. This stability was associated with peptide:MHCII-driven proliferation by a small number of T cells in the secondary lymphoid organs that harbored bacteria. The persistent population consisted of multi-functional Th1 cells that induced PD-1 and became exhausted when transferred to hosts expressing the specific peptide:MHCII ligand in all parts of the body. Thus, persistent infection of phagocytes produced a CD4+ T cell population that was stably maintained by low-level peptide:MHCII presentation.

CD4+T Cells: Guardians of the Phagosome

“…ϩ T cell population proliferate in response to the relevant p:MHCII ligand in secondary lymphoid organs or granulomas at any one time during the persistent phase of infection (113,115). This phenomenon is again likely related to the fact that only a small number of infected phagocytes are present in the body during this phase.…”

“…Another difference between the immune responses to persistent phagosomal infections and those to acute infections relates to the numerical stability of memory cells. The number of microbe p:MHCII-specific effector cells induced by phagosomal infections drops about 10-fold after the peak, as in the case of acute infections (111,113,115). Unlike the case of acute infections, however, the number of specific memory cells then remains constant in all body sites for hundreds of days (111,113,115).…”

“…The number of microbe p:MHCII-specific effector cells induced by phagosomal infections drops about 10-fold after the peak, as in the case of acute infections (111,113,115). Unlike the case of acute infections, however, the number of specific memory cells then remains constant in all body sites for hundreds of days (111,113,115). This remarkable stability is associated with low-level persistence of the phagosomal pathogen, as evidenced by the decline in the number of S. enterica p:MHCII-specific CD4 ϩ T cells after persistent infection was cleared with antibiotics (113,125).…”

“…Unlike the case of acute infections, however, the number of specific memory cells then remains constant in all body sites for hundreds of days (111,113,115). This remarkable stability is associated with low-level persistence of the phagosomal pathogen, as evidenced by the decline in the number of S. enterica p:MHCII-specific CD4 ϩ T cells after persistent infection was cleared with antibiotics (113,125). Thus, phagosomal pathogen p:MHCII-specific CD4 ϩ T cell populations are maintained by a nonclassical antigen-dependent mechanism.…”

Immunological memories of the bone marrow

“…Persisting antigen, even at low doses, could contribute to the maintenance of antigen‐experienced T cells in a chronic immune reaction 107. Long‐term maintenance of antigen has been demonstrated for follicular dendritic cells108 and even in the absence of any detectable pathogen after viral challenge, antigen can apparently persist in amounts sufficient to stimulate adoptively transferred, naive T cells 109…”