Hyaluronan‐binding by CD44 reduces the memory potential of activated murine CD8 T cells

Abstract

Expansion and death of effector CD8 T cells are regulated to limit immunopathology and cells that escape contraction go on to generate immunological memory. CD44, a receptor for the extracellular matrix component hyaluronan, is a marker of activated and memory T cells. Here, we show with a murine model that the increase in CD44 expression and hyaluronan binding induced upon CD8 T cell activation was proportional to the strength of TCR engagement, thereby identifying the most strongly activated T cells. When CD44 and CD44 OT-I CD8 T cells were adoptively transferred into mice challenged with Listeria-OVA, there was a slight increase in the percentage of CD44 cells at the effector site. However, CD44 cells were out-competed by CD44 cells after the contraction phase in the lymphoid tissues, and the CD44 cells preferentially formed more memory cells. The hyaluronan-binding CD44 CD8 effector T cells showed increased pAkt expression, higher glucose uptake, and were more susceptible to cell death during the contraction phase compared to non-binding CD44 and CD44 OT-I CD8 T cells, suggesting that CD44 and its engagement with hyaluronan skews CD8 T cells toward a terminal effector differentiation state that reduces their ability to form memory cells.

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“…Along both trajectories, we observed an upregulation of prominent T‐cell activation marker CD44, distinguishing T eff cells from their naïve counterparts. 46 As opposed to the T ex trajectory and consistent with previous studies, CD44 expression remained high in T cells along the T mem trajectory and an upregulation of memory marker expression (TOB1, ITM2C) was observed (Figure 4E ). 47 Along the CD8+ T ex trajectory, we observed high expression of immune checkpoints (PDCD1, HAVCR2, LAG3) and a decreased expression of cytotoxic‐activity genes (GZMB, PRF1, GNLY).…”

“…We observed two distinct trajectories: T n cells were connected to T eff cells, branching to form T mem or T ex cells (Figures 4C and D and S4G). Along both trajectories, we observed an upregulation of prominent T‐cell activation marker CD44, distinguishing T eff cells from their naïve counterparts 46 . As opposed to the T ex trajectory and consistent with previous studies, CD44 expression remained high in T cells along the T mem trajectory and an upregulation of memory marker expression (TOB1, ITM2C) was observed (Figure 4E).…”

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“…We next evaluated the ability of AH-PB to prime lung parenchyma-homing T cells. CD44 is a marker of activated and memory T cells [ 34 ]. In this study, the majority of lung CD44 + CD4 + T cells induced by intranasal AH-PB highly expressed the T RM markers CD69, CD103, or both, whereas T cells generated by BCG expressed these markers at a much lower frequency ( Figure 5(a,b) ).…”

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“…Using the relative abundances of T-cell subtype and activation markers allows us to determine shifts in T-cell populations across samples. In RE4, based on CD3-CD8-CD4-CD11c expression, some of the lymphocytes are effector T-cells also known as cytotoxic T-cells (CTLs) [ 31 ] and others are likely a subset of regulatory T-cells (Tregs) shown to suppress CD4+ T-cells [ 49 , 63 ]. RE2 and RE3 have similar protein expression profiles to RE4, however the lower CD11c expression and higher CD44 and suggest that the CTL:Treg ratio of present lymphocytes is higher [ 47 ].…”