Distinct CD4 ⁺ helper T cells involved in primary and secondary responses to infection

Abstract

Helper T cells are critical for protective immunity, CD8 + T-cell memory, and CD4 + recall responses, but whether the same or distinct CD4 + T cells are involved in these responses has not been established. Here we describe two CD4 + T cells, LLO118 and LLO56, specific for an immunodominant Listeria monocytogenes epitope, with dramatically different responses to primary and secondary infection. Comparing in vivo responses, LLO118 T cells proliferate more strongly to primary infection, whereas surprisingly, LLO56 has a superior CD4 + recall response to secondary infection. LLO118 T cells provide more robust help for CD8 + T-cell responses to secondary infection than LLO56. We found no detectable differences in antigen sensitivity, but naive LLO118 T cells have much lower levels of CD5 and their T-cell receptor levels are dramatically down-regulated after their strong primary response. Thus, distinct CD4 + helper T cells are specialized to help either in primary or secondary responses to infection.infectious disease | affinity | T-cell receptor transgenic mice | apoptosis C D4 + T cells are essential for CD8 + memory-cell formation, recall responses, and protective immunity (1-3). Despite the importance of CD4 + T cells in immune responses, studies examining T-cell responses to Listeria monocytogenes have focused primarily on CD8 + T cells (4). CD4 + T cells are not required for the primary CD8 + response to L. monocytogenes, but they play a critical role in the maintenance and survival of CD8 + memory cells (1-5). Memory cell formation is a hallmark of the adaptive immune system and successful memory cells must navigate expansion, contraction, and maintenance (6). Much more has been learned about the pathways for formation of CD8 + memory cells than CD4 + memory cells, but it is clear that the pathways for CD4 + memory formation are distinct (6-8). The parameters of optimal CD4 + help for CD8 + and CD4 + memory formation have not been characterized and represent an opportunity to effectively improve vaccines (9).T cells with shortened exposure to antigen do not successfully differentiate to memory cells (10). In contrast, overstimulation in a situation like chronic infection leads to T-cell exhaustion and ineffective memory cell formation or persistence (11). Thus, there appears to be a "goldilocks" level of T-cell stimulation for effective memory cell formation (6). Differences in the duration or abundance of antigen presentation or costimulatory molecules alter activation levels and T-cell receptor (TCR) levels and regulators on the T cell itself affect activation levels (12). TCR affinity and thymic development can also alter T-cell antigen sensitivity (13). For example, the surface expression of one Tcell-negative regulator of T-cell activation, CD5, correlates with the affinity of that developing TCR for self peptide (14-16). The relationship between effective CD4 + responses and the avidity of the TCR:pMHC interaction is not established and a polyclonal CD4 + T-cell population is not amenable to address the...

Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation

“…By comparing memory T cells generated after priming with either high dose/low affinity or low dose/high affinity antigen, our data additionally show that T cells with a similar history of primary expansion have a similar capacity to expand during secondary infection, independent of effector lineage. These data are consistent with a recent report showing an inverse correlation between primary T-cell expansion and memory T-cell development (40).…”

LysMD3 is a type II membrane protein without an role in the response to a range of pathogens

“…Antigen presentation by BMMo was assessed as described (86,87). BMMo were generated in 10% FBS and 10% CMG14-12 supernatant fluids (60) and infected with L. monocytogenes strain 10403S or pulsed with LLO peptide ± IFNγ priming.…”

“…At one HPI, infected BMMo were washed with Dulbecco's PBS and Gentamycin was added. Splenic CD4 T cells were isolated from LLO56tg mice (86), bearing a TCR specific for LLO190-225, were isolated using a CD4 negative selection kit (Miltenyi Biotech, Bergisch Gladbach, Germany) and added to the macrophage cultures. After 24 hours, cells were stained for CD4 (eFluor450, Clone RM4-5,…”

An Essential Role of the Avidity of T-Cell Receptor in Differentiation of Self-Antigen-reactive CD8+ T Cells

“…Weber and colleagues demonstrated that Listeria-specific T cells expressing distinct Listeria-specific TCRs with equal TCR avidity displayed different immune responses against Listeria infection in two transgenic (Tg) mice, and that it was caused by the difference in TCR avidity of Listeria-specific T cells to unknown self-antigens during thymic education. 44,45 It is well known that the strength of TCR avidity to unknown self-antigens in T cells can be evaluated by the levels of CD5 expression. 41,[46][47][48] In fact, notable difference was observed in CD5 expression between T cells from the two TCR-Tg mice described previously.…”