Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells

Abstract

The factors involved in the differentiation of memory CD4 T cells from naïve precursors are poorly understood. We developed a system to examine the effect of increased competition for antigen by CD4 T cells on the generation of memory in response to infection with a recombinant vesicular stomatitis virus. Competition was initially regulated by increasing the precursor frequency of adoptively transferred naïve T cell antigen receptor transgenic CD4 T cells. Despite robust proliferation at high precursor frequencies, memory CD4 T cells did not develop, whereas decreasing the input number of naïve CD4 T cells promoted memory development after infection. The lack of memory development was linked to reduced blastogenesis and poor effector cell induction, but not to initial recruitment or proliferation of antigen-specific CD4 T cells. To prove that availability of antigen alone could regulate memory CD4 T cell development, we used treatment with an mAb specific for the epitope recognized by the transferred CD4 T cells. At high doses, this mAb effectively inhibited the antigen-specific CD4 T cell response. However, at a very low dose of mAb, primary CD4 T cell expansion was unaffected, although memory development was dramatically reduced. Moreover, the induction of effector function was concomitantly inhibited. Thus, competition for antigen during CD4 T cell priming is a major contributing factor to the development of the memory CD4 T cell pool.infection ͉ effector ͉ differentiation ͉ precursor frequency

Distinct mechanisms mediate naïve and memory CD8 T-cell tolerance

“…To generate memory cells, CST BMC mice were infected i.v. with 1 × 10 5 pfu VSV-SED (41). Sixty days later, the mice were given doxycycline and subsequently analyzed as detailed in the text.…”

Early simultaneous production of intranodal CD4 Th2 effectors and recirculating rapidly responding central‐memory‐like CD4 T cells

“…Previous studies using adoptive transfer of transgenic T cells found that the initial number of transferred cells affects (i) quantitative and qualitative aspects of the T-cell differentiation [33,34], (ii) central and effector memory commitment [20], (iii) survival of T memory cells [21,22], (iv) proliferation, phenotype and acquisition of effector functions [33], (v) expansion, peak and contraction phases of the T-cell immune response [34] as well as (vi) CD62L expression on recirculating T cells [35]. These findings made it necessary to assess whether the appearance of early primed emigrant OT-II cells occurs only in the presence of high numbers of Ag-specific naïve CD4 T cells.…”

“…Given that high initial precursor frequency may be detrimental to the survival of memory T cells [21,22] we assessed late Although memory cells persist after all levels of initial transfer, there is a pro rata reduction in the number of CFSE low cells recovered from the mice that have received fewer initial OT-II cells. This finding means that the catch-up of cell number seen at 7 d into the primary response in the mice that originally received low numbers of OT-II (Fig.…”

“…In addition to early memory formation there is production of effector helpers that produce Th2 cytokines [16] and direct B cells to undergo Ig class switching and to form plasmablasts and germinal centers [17][18][19]. Finally, the effect of the initial T-cell precursor frequency has been considered, for evidence has emerged that this can influence central and effector memory commitment [20], and memory T-cell survival [21,22].…”

Human CD4+ effector T lymphocytes generated upon TCR engagement with self-peptides respond defectively to IL-7 in their transition to memory cells

“…Limited amounts of Ag, as well as non physiologically high precursor frequency of Ag-specific naive T cells competing for antigen presenting cells interactions or nutrients, results in defective memory formation. 22,23 Therefore, and according to the quality and strength of differentiation signals, it is feasible that memory cells generated by stimulation with self-Ag would differ from memory lymphocytes generated upon activation with their nominal Ag. In the present study, we analysed whether human primary effector CD4…”